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12,163	s truct ura l formula PENTASA® (mesalamine) Controlled-Release Capsules 250 mg and 500 mg Prescribing Information as of July 2013 Rx only DESCRIPTION PENTASA (mesalamine) for oral administration is a controlled-release formulation of mesalamine, an aminosalicylate anti-inflammatory agent for gastrointestinal use. Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid. It has a molecular weight of 153.14. The structural formula is: Each 250 mg capsule contains 250 mg of mesalamine. It also contains the following inactive ingredients: acetylated monoglyceride, castor oil, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, starch, stearic acid, sugar, talc, and white wax. The capsule shell contains D&C Yellow #10, FD&C Blue #1, FD&C Green #3, gelatin, titanium dioxide, and other ingredients. Each 500 mg capsule contains 500 mg of mesalamine. It also contains the following inactive ingredients: acetylated monoglyceride, castor oil, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, starch, stearic acid, sugar, talc, and white wax. The capsule shell contains FD&C Blue #1, gelatin, titanium dioxide, and other ingredients. CLINICAL PHARMACOLOGY Sulfasalazine is split by bacterial action in the colon into sulfapyridine (SP) and mesalamine (5-ASA). It is thought that the mesalamine component is therapeutically active in ulcerative colitis. The usual oral dose of sulfasalazine for active ulcerative colitis in adults is 2 to 4 g per day in divided doses. Four grams of sulfasalazine provide 1.6 g of free mesalamine to the colon. The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, ie, prostanoids, and through the lipoxygenase pathways, ie, leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine 1 Reference ID: 3422464 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon. Human Pharmacokinetics and Metabolism Absorption. PENTASA is an ethylcellulose-coated, controlled-release formulation of mesalamine designed to release therapeutic quantities of mesalamine throughout the gastrointestinal tract. Based on urinary excretion data, 20% to 30% of the mesalamine in PENTASA is absorbed. In contrast, when mesalamine is administered orally as an unformulated 1-g aqueous suspension, mesalamine is approximately 80% absorbed. Plasma mesalamine concentration peaked at approximately 1 µg/mL 3 hours following a 1-g PENTASA dose and declined in a biphasic manner. The literature describes a mean terminal half-life of 42 minutes for mesalamine following intravenous administration. Because of the continuous release and absorption of mesalamine from PENTASA throughout the gastrointestinal tract, the true elimination half-life cannot be determined after oral administration. N-acetylmesalamine, the major metabolite of mesalamine, peaked at approximately 3 hours at 1.8 µg/mL, and its concentration followed a biphasic decline. Pharmacological activities of N-acetylmesalamine are unknown, and other metabolites have not been identified. Oral mesalamine pharmacokinetics were nonlinear when PENTASA capsules were dosed from 250 mg to 1 g four times daily, with steady-state mesalamine plasma concentrations increasing about nine times, from 0.14 µg/mL to 1.21 µg/mL, suggesting saturable first-pass metabolism. N-acetylmesalamine pharmacokinetics were linear. Elimination. About 130 mg free mesalamine was recovered in the feces following a single 1-g PENTASA dose, which was comparable to the 140 mg of mesalamine recovered from the molar equivalent sulfasalazine tablet dose of 2.5 g. Elimination of free mesalamine and salicylates in feces increased proportionately with PENTASA dose. N-acetylmesalamine was the primary compound excreted in the urine (19% to 30%) following PENTASA dosing. CLINICAL TRIALS In two randomized, double-blind, placebo-controlled, dose-response trials (UC-1 and UC-2) of 625 patients with active mild to moderate ulcerative colitis, PENTASA, at an oral dose of 4 g/day given 1 g four times daily, produced consistent improvement in prospectively identified primary efficacy parameters, PGA, Tx F, and SI as shown in the table below. The 4-g dose of PENTASA also gave consistent improvement in secondary efficacy parameters, namely the frequency of trips to the toilet, stool consistency, rectal bleeding, abdominal/rectal pain, and urgency. The 4-g dose of PENTASA induced remission as assessed by endoscopic and symptomatic endpoints. In some patients, the 2-g dose of PENTASA was observed to improve efficacy parameters measured. However, the 2-g dose gave inconsistent results in primary efficacy parameters across the two adequate and well-controlled trials. 2 Reference ID: 3422464 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parameter Evaluated Clinical Trial UC-1 Clinical Trial-UC-2 PL (n=90) PENTASA PL (n=83) PENTASA 4 g/day (n=95) 2 g/day (n=97) 4 g/day (n=85) 2 g/day (n=83) PGA 36% 59%* 57%* 31% 55%* 41% Tx F 22% 9%* 18% 31% 9%* 17%* SI -2.5 -5.0* -4.3* -1.6 -3.8* -2.6 Remission† 12% 26%* 24%* 12% 27%* 12% * p<0.05 vs placebo. PGA: Physician Global Assessment: proportion of patients with complete or marked improvement. Tx F: Treatment Failure: proportion of patients developing severe or fulminant UC requiring steroid therapy or hospitalization or worsening of the disease at 7 days of therapy, or lack of significant improvement by 14 days of therapy. SI: Sigmoidoscopic Index: an objective measure of disease activity rated by a standard (15-point) scale that includes mucosal vascular pattern, erythema, friability, granularity/ulcerations, and mucopus: improvement over baseline. † Defined as complete resolution of symptoms plus improvement of endoscopic endpoints. To be considered in remission, patients had a “1” score for one of the endoscopic components (mucosal vascular pattern, erythema, granularity, or friability) and “0” for the others. INDICATIONS AND USAGE PENTASA is indicated for the induction of remission and for the treatment of patients with mildly to moderately active ulcerative colitis. CONTRAINDICATIONS PENTASA is contraindicated in patients who have demonstrated hypersensitivity to mesalamine, any other components of this medication, or salicylates. PRECAUTIONS General Caution should be exercised if PENTASA is administered to patients with impaired hepatic function. Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence cannot be ascertained, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, prompt withdrawal is required. If a rechallenge is performed later in order to 3 Reference ID: 3422464 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda validate the hypersensitivity, it should be carried out under close medical supervision at reduced dose and only if clearly needed. Renal Caution should be exercised if PENTASA is administered to patients with impaired renal function. Single reports of nephrotic syndrome and interstitial nephritis associated with mesalamine therapy have been described in the foreign literature. There have been rare reports of interstitial nephritis in patients receiving PENTASA. In animal studies, a 13-week oral toxicity study in mice and 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys have shown the kidney to be the major target organ of mesalamine toxicity. Oral daily doses of 2400 mg/kg in mice and 1150 mg/kg in rats produced renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, oral daily doses of 250 mg/kg or higher produced nephrosis, papillary edema, and interstitial fibrosis. Patients with preexisting renal disease, increased BUN or serum creatinine, or proteinuria should be carefully monitored, especially during the initial phase of treatment. Mesalamine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment. Interference with Laboratory Tests Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection, because of the similarity in the chromatograms of normetanephrine and mesalamine’s main metabolite, N acetylaminosalicylic acid (N-Ac-5-ASA). An alternative, selective assay for normetanephrine should be considered. Drug Interactions There are no data on interactions between PENTASA and other drugs. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week dietary carcinogenicity study of mesalamine, CD-1 mice were treated with doses up to 2500 mg/kg/day and it was not tumorigenic. For a 50 kg person of average height (1.46 m2 body surface area), this represents 2.5 times the recommended human dose on a body surface area basis (2960 mg/m2/day). In a 104-week dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800 mg/kg/day was not tumorigenic. This dose represents 1.5 times the recommended human dose on a body surface area basis. No evidence of mutagenicity was observed in an in vitro Ames test and in an in vivo mouse micronucleus test. No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 400 mg/kg/day (0.8 times the recommended human dose based on body surface area). Semen abnormalities and infertility in men, which have been reported in association with sulfasalazine, have not been seen with PENTASA capsules during controlled clinical trials. 4 Reference ID: 3422464 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 1000 mg/kg/day (5900 mg/M²) and rabbits at doses of 800 mg/kg/day (6856 mg/M²) and have revealed no evidence of teratogenic effects or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PENTASA should be used during pregnancy only if clearly needed. Mesalamine is known to cross the placental barrier. Nursing Mothers Minute quantities of mesalamine were distributed to breast milk and amniotic fluid of pregnant women following sulfasalazine therapy. When treated with sulfasalazine at a dose equivalent to 1.25 g/day of mesalamine, 0.02 μg/mL to 0.08 μg/mL and trace amounts of mesalamine were measured in amniotic fluid and breast milk, respectively. N acetylmesalamine, in quantities of 0.07 μg/mL to 0.77 μg/mL and 1.13 μg/mL to 3.44 µg/mL, was identified in the same fluids, respectively. Caution should be exercised when PENTASA is administered to a nursing woman. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions like diarrhea in the infant cannot be excluded. Pediatric Use Safety and efficacy of PENTASA in pediatric patients have not been established. ADVERSE REACTIONS In combined domestic and foreign clinical trials, more than 2100 patients with ulcerative colitis or Crohn’s disease received PENTASA therapy. Generally, PENTASA therapy was well tolerated. The most common events (ie, greater than or equal to 1%) were diarrhea (3.4%), headache (2.0%), nausea (1.8%), abdominal pain (1.7%), dyspepsia (1.6%), vomiting (1.5%), and rash (1.0%). In two domestic placebo-controlled trials involving over 600 ulcerative colitis patients, adverse events were fewer in PENTASA® (mesalamine)-treated patients than in the placebo group (PENTASA 14% vs placebo 18%) and were not dose-related. Events occurring at 1% or more are shown in the table below. Of these, only nausea and vomiting were more frequent in the PENTASA group. Withdrawal from therapy due to adverse events was more common on placebo than PENTASA (7% vs 4%). 5 Reference ID: 3422464 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Adverse Events Occurring in More than 1% of Either Placebo or PENTASA Patients in Domestic Placebo-controlled Ulcerative Colitis Trials. (PENTASA Comparison to Placebo) Event PENTASA n=451 Placebo n=173 Diarrhea 16 (3.5%) 13 (7.5%) Headache 10 (2.2%) 6 (3.5%) Nausea 14 (3.1%) ----- Abdominal Pain 5 (1.1%) 7 (4.0%) Melena (Bloody Diarrhea) 4 (0.9%) 6 (3.5%) Rash 6 (1.3%) 2 (1.2%) Anorexia 5 (1.1%) 2 (1.2%) Fever 4 (0.9%) 2 (1.2%) Rectal Urgency 1 (0.2%) 4 (2.3%) Nausea and Vomiting 5 (1.1%) ----- Worsening of Ulcerative Colitis 2 (0.4%) 2 (1.2%) Acne 1 (0.2%) 2 (1.2%) Clinical laboratory measurements showed no significant abnormal trends for any test, including measurement of hematological, liver, and kidney function. The following adverse events, presented by body system, were reported infrequently (ie, less than 1%) during domestic ulcerative colitis and Crohn’s disease trials. In many cases, the relationship to PENTASA has not been established. Gastrointestinal: abdominal distention, anorexia, constipation, duodenal ulcer, dysphagia, eructation, esophageal ulcer, fecal incontinence, GGTP increase, GI bleeding, increased alkaline phosphatase, LDH increase, mouth ulcer, oral moniliasis, pancreatitis, rectal bleeding, SGOT increase, SGPT increase, stool abnormalities (color or texture change), thirst Dermatological: acne, alopecia, dry skin, eczema, erythema nodosum, nail disorder, photosensitivity, pruritus, sweating, urticaria Nervous System: depression, dizziness, insomnia, somnolence, paresthesia Cardiovascular: palpitations, pericarditis, vasodilation Other: albuminuria, amenorrhea, amylase increase, arthralgia, asthenia, breast pain, conjunctivitis, ecchymosis, edema, fever, hematuria, hypomenorrhea, Kawasaki-like syndrome, leg cramps, lichen planus, lipase increase, malaise, menorrhagia, metrorrhagia, myalgia, pulmonary infiltrates, thrombocythemia, thrombocytopenia, urinary frequency One week after completion of an 8-week ulcerative colitis study, a 72-year-old male, with no previous history of pulmonary problems, developed dyspnea. The patient was subsequently diagnosed with interstitial pulmonary fibrosis without eosinophilia by one physician and 6 Reference ID: 3422464 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda bronchiolitis obliterans with organizing pneumonitis by a second physician. A causal relationship between this event and mesalamine therapy has not been established. Published case reports and/or spontaneous postmarketing surveillance have described infrequent instances of pericarditis, fatal myocarditis, chest pain and T-wave abnormalities, hypersensitivity pneumonitis, pancreatitis, nephrotic syndrome, interstitial nephritis, hepatitis, aplastic anemia, pancytopenia, leukopenia, agranulocytosis, or anemia while receiving mesalamine therapy. Anemia can be a part of the clinical presentation of inflammatory bowel disease. Allergic reactions, which could involve eosinophilia, can be seen in connection with PENTASA therapy. Postmarketing Reports The following events have been identified during post-approval use of the PENTASA brand of mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine: Gastrointestinal: Reports of hepatotoxicity, including elevated liver enzymes (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), hepatitis, jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome which included hepatic function changes was also reported. Other: Postmarketing reports of anaphylactic reaction, Steven-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), pneumonitis, granulocytopenia, systemic lupus erythematosis, acute renal failure, chronic renal failure and angioedema have been received in patients taking PENTASA. OVERDOSAGE Single oral doses of mesalamine up to 5 g/kg in pigs or a single intravenous dose of mesalamine at 920 mg/kg in rats were not lethal. There is no clinical experience with PENTASA overdosage. PENTASA is an aminosalicylate, and symptoms of salicylate toxicity may be possible, such as: tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation, vomiting, and diarrhea. Severe intoxication with salicylates can lead to disruption of electrolyte balance and blood- pH, hyperthermia, and dehydration. Treatment of Overdosage. Since PENTASA is an aminosalicylate, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. This includes prevention of further gastrointestinal tract absorption by emesis and, if necessary, by gastric lavage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should be maintained. 7 Reference ID: 3422464 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION The recommended dosage for the induction of remission and the symptomatic treatment of mildly to moderately active ulcerative colitis is 1g (4 PENTASA 250 mg capsules or 2 PENTASA 500 mg capsules) 4 times a day for a total daily dosage of 4g. Treatment duration in controlled trials was up to 8 weeks. HOW SUPPLIED PENTASA controlled-release 250 mg capsules are supplied in bottles of 240 capsules (NDC 54092-189-81). Each green and blue capsule contains 250 mg of mesalamine in controlled- release beads. PENTASA controlled-release capsules are identified with a pentagonal starburst logo and the number 2010 on the green portion and PENTASA 250 mg or S429 250 mg on the blue portion of the capsules. PENTASA controlled-release 500 mg capsules are supplied in bottles of 120 capsules (NDC 54092-191-12). Each blue capsule contains 500 mg of mesalamine in controlled-release beads. PENTASA controlled-release capsules are identified with a pentagonal starburst logo and PENTASA 500 mg or S429 500 mg on the capsules. Store at 25˚C (77˚F); excursions permitted to 15-30˚C (59-86˚F) [see USP Controlled Room Temperature]. Manufactured for Shire US Inc. 725 Chesterbrook Blvd., Wayne, PA 19087, USA PENTASA is a registered trademark of Ferring B.V.  2013 Shire US Inc. Rev. 08/2013 8 Reference ID: 3422464 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:33.563232	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020049s026lbl.pdf', 'application_number': 20049, 'submission_type': 'SUPPL ', 'submission_number': 26}
12,166	DO NOT USE IF IMPRINTED NECKBAND IS NOT INTACT. EXP LOT DO NOT USE IF IMPRINTED NECKBAND IS NOT INTACT. 0.5 FL OZ (15 mL) www.bausch.com With antihistamine to relieve itching Original prescription strength Allergy When using this product ■ overuse may cause more eye redness ■ pupils may become enlarged temporarily ■ do not touch tip of container to any surface to avoid contamination ■ you may feel a brief tingling after putting drops in eye ■ replace cap after use ■ remove contact lenses before using Stop use and ask a doctor if you experience ■ eye pain ■ changes in vision ■ redness or irritation of the eye that worsens or lasts more than 72 hours. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Accidental oral ingestion in infants and children may lead to coma and marked reduction in body temperature. Directions ■ Adults and children 6 years of age and older: Instill 1 or 2 drops in the affected eye(s) up to 4 times daily. ■ Children under 6 years: ask a doctor Other information ■ store at 20°-25°C (68°- 77°F) ■ protect from light Drug Facts (continued) Bausch & Lomb and Opcon-A are registered trademarks of Bausch & Lomb Incorporated © Bausch & Lomb Incorporated Rochester, NY 14609 100% SATISFACTION GUARANTEED. See inside of carton for details. Order No. 622090 Questions or Comments? Toll Free Product Information Call: 1-800-553-5340 3 6 10119 02090 Opcon-A ® PHENIRAMINE MALEATE 0.315% AND NAPHAZOLINE HYDROCHLORIDE 0.02675% OPHTHALMIC SOLUTION ITCHING AND REDNESS RELIEVER EYE DROPS Opcon-A ® PHENIRAMINE MALEATE 0.315% AND NAPHAZOLINE HYDROCHLORIDE 0.02675% OPHTHALMIC SOLUTION ITCHING AND REDNESS RELIEVER EYE DROPS Drug Facts Active Purpose ingredients Naphazoline HCI Redness (0.02675%)...........reliever Pheniramine maleate (0.315%).....Antihistamine Uses ■ temporarily relieves itching and redness caused by pollen, ragweed, grass, animal hair and dander. Warnings Do not use ■ if you are sensitive to any ingredient in this product ■ if solution changes color or becomes cloudy Ask a doctor before use if you have ■ heart disease ■ high blood pressure ■ trouble urinating due to an enlarged prostate gland ■ narrow angle glaucoma Drug Facts (continued) ■ use before expiration date marked on the carton or bottle Inactive ingredients benzalkonium chloride, boric acid, edetate disodium, hypromellose, purified water, sodium borate, sodium chloride This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Facts - 14 point Helvetica Bold Italic Condensed Oblique Drug Facts - 8 point Helvetica Italic Bold Condensed Oblique (continued) - 8 point Helvetica Bold Condensed Oblique Headings - 8 point Helvetica Bold Italic Condensed Oblique Subheadings - 6 point Helvetica Bold Condensed Oblique Body Text - 6 point Helvetica Bold Condensed Oblique Bullets - 5 point square Boxline - 2.5 point Hairline - 0.5 point Allergy Opcon-A ® PHENIRAMINE MALEATE 0.315% AND NAPHAZOLINE HYDROCHLORIDE 0.02675% OPHTHALMIC SOLUTION ITCHING AND REDNESS RELIEVER EYE DROPS 0.5 FL OZ (15mL) 6300309 ACTIVE INGREDIENTS: Naphazoline HCI (0.02675%), Pheniramine maleate (0.315%). USES: Temporarily relieves itching and redness caused by pollen, ragweed, grass, animal hair and dander. DIRECTIONS: Adults and children 6 years of age and older: Instill 1 or 2 drops in the affected eye(s) up to 4 times daily. Children under 6 years: Ask a doctor WARNINGS: If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours, discontinue use and consult a physician. Do not use in children under 6 years of age unless directed by a physician. If this solution changes color or becomes cloudy, do not use. Overuse of this product may produce increased redness of the eye. Keep out of reach of children. REMOVE CONTACT LENSES BEFORE USING. See carton for additional WARNINGS. Store at 20°-25°C (68°-77°F). Protect from light. Toll Free Product Information Call: 1-800-553-5340 Bausch & Lomb and Opcon-A are registered trademarks of Bausch & Lomb Incorporated. © Bausch & Lomb Incorporated Bausch & Lomb, Rochester, NY 14609 DO NOT USE IF IMPRINTED NECKBAND IS NOT INTACT. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:33.889194	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020065s017lbl.pdf', 'application_number': 20065, 'submission_type': 'SUPPL ', 'submission_number': 17}
12,167		custom-source	2025-02-12T13:46:33.921748	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20-066S010_Nicorette_prntlbl.pdf', 'application_number': 20066, 'submission_type': 'SUPPL ', 'submission_number': 10}
12,171	0 0 0000-0000-00 Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 PIECES, 2mg EACH Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OPEN HERE Peel off backing, starting at corner with loose edge. To remove the gum, tear off single unit. Push gum through foil. 10 PIECES, 4mg EACH Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3522999 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:35.533059	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018612Orig1s072, s073, 020066Orig1s053, s054lbl .pdf', 'application_number': 20066, 'submission_type': 'SUPPL ', 'submission_number': 54}
12,170	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. keys to success. 1) You must really want to quit smoking for Nicorette® Gum to help you. 2) You can greatly increase your chances for success by using at least 9 to 12 pieces every day when you start using Nicorette Gum. See page 12. 3) You should continue to use Nicorette Gum as explained in this User’s Guide for 12 full weeks. If you feel you need to use Nicorette Gum for a longer period to keep from smoking, talk to your health care provider. 4) Nicorette Gum works best when used together with a support program — See page 3 for details. 5) If you have trouble using Nicorette Gum, ask your doctor or pharmacist or call GlaxoSmithKline at 1-800-419-4766 weekdays (10:00 am - 4:30 pm ET). 6) To request a free audio CD containing tips to help make quitting easier, call the toll free number listed above. (ONE CD PER CUSTOMER) 1 3599255 NRO Gum UGuide_R1_V2 indd 3 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 2 SO YOU DECIDED TO QUIT. If you’ve tried to quit before and haven’t succeeded, don’t be discouraged! Quitting isn’t easy. It takes time, and most people try a few times before they are successful. The important thing is to try again until you succeed. This User’s Guide will give you support as you become a non-smoker. It will answer common questions about Nicorette Gum and give tips to help you stop smoking, and should be referred to often. Congratulations. Your decision to stop smoking is an important one. That’s why you’ve made the right choice in choosing Nicorette Gum. Your own chances of quitting smoking depend on how much you want to quit, how strongly you are addicted to tobacco, and how closely you follow a quitting program like the one that comes with Nicorette Gum. QuittinG Smoking is hard! 3599255 NRO Gum UGuide_R1_V2 indd 4 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 3 If you ﬁ nd you cannot stop smoking or if you start smoking again after using Nicorette Gum, remember breaking this addiction doesn’t happen overnight. You may want to talk to a health care professional who can help you improve your chances of quitting the next time you try Nicorette Gum or another method. Your reason for quitting may be a combination of concerns about health, the effect of smoking on your appearance, and pressure from your family You are more likely to stop smoking by using Nicorette Gum with a support program that helps you break your smoking habit. There may be support groups in your area for people trying to quit. Call your local chapter of the American Lung Association, American Cancer Society or American Heart Association for further information. Toll free phone numbers are printed on the Wallet Card on the back cover of this User’s Guide. LET’S GET ORGaNIZED. where to get help. 3599255 NRO Gum UGuide_R1_V2 indd 5 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. Smoking is addictive in two ways. Your need for nicotine has become both physical and mental. You must overcome both addictions to stop smoking. So while Nicorette Gum will lessen your body’s physical addiction to nicotine, you’ve got to want to quit smok- ing to overcome the mental dependence on cigarettes. Once you’ve decided that you’re going to quit, it’s time to get started. But ﬁ rst, there are some important warn- ings you should consider. and friends to stop smoking. Or maybe you’re concerned about the dangerous effect of second-hand smoke on the people you care about. All of these are good reasons. You probably have others. Decide your most important reasons, and write them down on the wallet card inside the back cover of this User’s Guide. Carry this card with you. In difﬁ cult moments, when you want to smoke, the card will remind you why you are quitting. WHAT YOU’RE UP AGAINST. 4 3599255 NRO Gum UGuide_R1_V2 indd 6 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. This product is only for those who want to stop smoking. If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Some important WARNINGS. Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. • high blood pressure not controlled with medication. Nicotine can increase your blood pressure. • stomach ulcer or diabetes 5 3599255 NRO Gum UGuide_R1_V2 indd 7 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 6 Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking a prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if • mouth, teeth or jaw problems occur • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat • you have symptoms of an allergic reaction (such as difﬁ culty breathing or rash) Keep out of reach of children and pets. Pieces of nicotine gum may have enough nico- tine to make children and pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. Becoming a non-smoker starts today. First, check that you bought the right starting dose. If you smoke your ﬁ rst cigarette within 30 minutes of waking up, use 4mg nicotine gum. If you smoke your ﬁ rst cigarette more LET’S GET STARTED. 3599255 NRO Gum UGuide_R1_V2 indd 8 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 7 than 30 minutes after waking up, use 2mg nicotine gum. Next, read through the en- tire User’s Guide carefully. Then, set your personalized quitting schedule. Take out a calendar that you can use to track your progress, and identify four dates, using the stickers in the center of this User’s Guide: STEP 1. (Weeks 1-6). Your quit date (and the day you’ll start using Nicorette Gum). Choose your quit date (it should be soon). This is the day you will begin using Nicorette Gum to satisfy your cravings for nicotine. For the ﬁ rst six weeks, you’ll use a piece of Nicorette Gum every hour or two. Be sure to follow the directions starting on pages 10 and 12. Place the Step 1 stickers on this date. STEP 2. (Weeks 7 to 9). The day you’ll start reducing your use of Nicorette Gum. After six weeks, you’ll begin gradually reducing your Nicorette Gum usage to one piece every two to four hours. Place the Step 2 sticker on this date (the ﬁ rst day of week seven). STEP 3. (Weeks 10-12). The day you’ll further reduce your use of Nicorette Gum. 3599255 NRO Gum UGuide_R1_V2 indd 9 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 8 Nine weeks after you begin using Nicorette Gum, you will further reduce your nicotine intake by using one piece every four to eight hours. Place the Step 3 sticker on this date (the ﬁ rst day of week ten). For the next three weeks, you’ll use a piece of Nicorette Gum every four to eight hours. End of treatment: The day you’ll complete Nicorette Gum therapy. Identify the date thirteen weeks after the date you chose in Step 1, and place the “EX-SMOKER” sticker on your calendar. Because smoking is an addiction, it is not easy to stop. After you’ve given up cigarettes, you will still have a strong urge to smoke. Plan ahead NOW for these times, so you’re not defeated in a moment of weakness. The following tips may help: • Keep the phone numbers of supportive friends and family members handy. • Keep a record of your quitting process. Track the number of Nicorette Gum pieces you use each day, and whether you feel a craving for cigarettes. In the event that PLAN AHEAD. 3599255 NRO Gum UGuide_R1_V2 indd 10 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 9 you slip, immediately stop smoking and resume your quit attempt with the Nicorette Gum program. • Put together an Emergency Kit that includes items that will help take your mind off occasional urges to smoke. Include cinnamon gum or lemon drops to suck on, a relaxing CD, and something for your hands to play with, like a smooth rock, rubber band, or small metal balls. • Set aside some small rewards, like a new magazine or a gift certiﬁ cate from your favorite store, which you’ll “give” yourself after passing difﬁ cult hurdles. • Think now about the times when you most often want a cigarette, and then plan what else you might do instead of smoking. For instance, you might plan to take your coffee break in a new location, or take a walk right after dinner, so you won’t be tempted to smoke. 3599255 NRO Gum UGuide_R1_V2 indd 11 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. the addictive part of cigarette smoke. Nicotine can cause side effects such as headache, nausea, upset stomach, and dizziness. If you are under 18 years of age, ask a doctor before use. Before you can use Nicorette Gum correctly, you have to prac- tice! That sounds silly, but it isn’t. Nicorette Gum isn’t like ordinary chewing gum. It’s a medicine, and must be chewed a certain way to work right. Chewed like ordinary gum, Nicorette Gum won’t work well and Nicorette Gum’s sug- ar-free chewing pieces provide nicotine to your system – they work as a temporary aid to help you quit smoking by reducing nicotine withdrawal symptoms. Nicorette Gum provides a lower level of nicotine to your blood than ciga- rettes, and allows you to gradually do away with your body’s need for nicotine. Because Nicorette Gum does not contain the tar or carbon monoxide of cigarette smoke, it does not have the same health dangers as tobacco. However, it still delivers nicotine, 10 HOW NICOrette gum works. HOW To Use NICOrette gum. 3599255 NRO Gum UGuide_R1_V2 indd 12 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. can cause side effects. An overdose can occur if you chew more than one piece of Nicorette Gum at the same time, or if you chew many pieces one after another. Read all the following instructions before using Nicorette Gum. Refer to them often to make sure you’re using Nicorette Gum correctly. If you chew too fast, or do not chew correctly, you may get hiccups, heart- burn, or other stomach problems. Don’t eat or drink for 15 minutes before using Nicorette Gum, or while chewing a piece. The effectiveness of Nicorette Gum may be reduced by some foods and drinks, such as 11 coffee, juices, wine or soft drinks. 1) Begin using Nicorette Gum on your quit day. 2) To reduce craving and other withdrawal symptoms, use Nicorette Gum according to the dosage schedule on page 12. 3) Chew each Nicorette Gum piece very slowly several times. 4) Stop chewing when you notice a peppery taste, or a slight tingling in your mouth. (This usually happens after about 15 chews, but may vary from person to person.) 3599255 NRO Gum UGuide_R1_V2 indd 13 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 12 5) “PARK” the Nicorette Gum piece between your cheek and gum, and leave it there. 6) When the peppery taste or tingle is almost gone (in about a minute), start to chew a few times slowly again. When the taste or tingle returns, stop again. 7) Park the Nicorette Gum piece again (in a different place in your mouth). 8) Repeat steps 3 to 7 (chew, chew, park) until most of the nicotine is gone from the Nicorette Gum piece (usually happens in about half an hour; the peppery taste or tingle won’t return.) 9) Wrap the used Nicorette Gum piece in paper and throw away in the trash. To improve your chances of quitting, use at least 9 pieces of Nicorette Gum a day. If you experience strong or frequent cravings, you may use a second piece within the hour. However, do not continuously use one The following chart lists the recommended usage schedule for Nicorette Gum: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 piece every 1 piece every 1 piece every 1 to 2 hours 2 to 4 hours 4 to 8 hours DO NOT USE MORE THAN 24 PIECES PER DAY. 3599255 NRO Gum UGuide_R1_V2 indd 14 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHEN YOU CALL: You will be asked a few questions to understand YOU and YOUR speciﬁ c needs. AFTER YOU CALL: In a few days, you will receive your custom-tailored stop smoking plan. You will continue to receive personal, custom-tailored support — six times during the next twelve weeks. 3599255 NRO Gum UGuide_R1_V2 indd 17 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How To Survive the First Week: Quitting Tips 3. Stay active. Keep busy to take your mind off smoking. 4. Think positive! The ﬁ rst week is the toughest. Remind yourself that it will get easier. Use the sample of the Stop Smoking Plan (see next page) to get you through the ﬁ rst week until your materials arrive. 1. Control your physical cravings for nicotine. Use enough – You can greatly increase your chances for success by using at least 9 to 12 pieces every day when you start using Nicorette Gum. 2. Get rid of all signs that you ever smoked — ashtrays, matches and, of course, cigarettes. 3599255 NRO Gum UGuide_R1_V2 indd 20 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ©2013 GlaxoSmithKline The Committed Quitters ® program is a plan speciﬁ cally individualized for you. Call Between 7 am and 12 Midnight ET or enroll online 24 hours a day. (ONE PLAN PER CUSTOMER) NICORETTE and COMMITTED QUITTERS are registered trademarks, and associated logo designs and overall dress designs are trademarks owned and/or licensed to the GlaxoSmithKline group of companies. Read and follow label directions 3599255 NRO Gum UGuide_R1_V2 indd 22 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 13 piece after another, since this may cause you hiccups, heartburn, nausea or other side effects. The goal of using Nicorette Gum is to slowly reduce your dependence on nico- tine. The schedule for using Nicorette Gum will help you reduce your nicotine craving gradually as you reduce and then stop your use of Nicorette Gum. Here are some tips to help you cut back during each step and then stop using Nicorette Gum: HOW to reduce your nicorette GUM usage. • After a while, start chewing each Nicorette Gum piece for only 10 to 15 minutes, instead of half an hour. Then, gradually begin to reduce the number of pieces used. • Or, try chewing each piece for longer than half an hour, but reduce the number of pieces you use each day. • Substitute ordinary chewing gum for some of the Nicorette Gum pieces you would normally use. Increase the number of pieces of ordinary gum as you cut back on the Nicorette Gum pieces. 3599255 NRO Gum UGuide_R1_V2 indd 23 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 14 • Check how well you’ve reduced your daily usage of Nicorette Gum in Weeks 10 to 12. You should only be using about 3 to 5 pieces a day. Get ready to stop. The following tips may help you try to stop Nicorette Gum when you have completed treatment. • Set a stop date. • Use the same number of pieces of confectionery gum or mints as you were using Nicorette Gum per day. At the times when you have an urge to use Nicorette Gum, use a strong ﬂ avored gum or mint such as cinnamon or peppermint. • Reduce the number of pieces of gum or mints you use by one piece per day until you do not need to use any gum or mints. Talk to your doctor or health care provider if you: • still feel the need to use Nicorette Gum at the end of week 12 to keep from smoking • start using Nicorette Gum again after stopping • start smoking again 3599255 NRO Gum UGuide_R1_V2 indd 24 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 15 Within the ﬁ rst few weeks of giving up smoking, you may be tempted to smoke for pleasure, particularly after completing a difﬁ cult task, or at a party or bar. Here are some tips to help get you through the important ﬁ rst stages of becoming a non-smoker: On Your Quit Date: • Ask your family, friends and co-workers to support you in your efforts to stop smoking. TIPS TO MAKE QUITTING EASIER. • Throw away all your cigarettes, matches, lighters, ashtrays, etc. • Keep busy on your quit day. Exercise. Go to a movie. Take a walk. Get together with friends. • Figure out how much money you’ll save by not smoking. Most ex-smokers can save more than $1,000 a year. • Write down what you will do with the money you save. 3599255 NRO Gum UGuide_R1_V2 indd 25 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 16 • Know your high risk situations and plan ahead how you will deal with them. • Keep Nicorette Gum near your bed, so you’ll be prepared for any nicotine cravings when you wake up in the morning. • Visit your dentist and have your teeth cleaned to get rid of the tobacco stains. Right after Quitting: • During the ﬁ rst few days after you’ve stopped smoking, spend as much time as possible at places where smoking is not allowed. • Drink large quantities of water and fruit juices. • Try to avoid alcohol, coffee and other beverages you associate with smoking. • Remember that temporary urges to smoke will pass, even if you don’t smoke a cigarette. • Keep your hands busy with something like a pencil or a paper clip. • Find other activities which help you relax without cigarettes. • Swim, jog, take a walk, play basketball. 3599255 NRO Gum UGuide_R1_V2 indd 26 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 17 stop smoking, you might feel edgy and nervous and have trouble concentrating. You might get headaches, feel dizzy and a little out of sorts, feel sweaty or have stomach upsets. You might even have trouble sleeping at ﬁ rst. These are typical withdrawal symptoms that will go away with time. Your smoker’s cough will get worse before it gets better. But don’t worry, that’s a good sign. Coughing helps clear the tar deposits out of your lungs. what to expect. • Don’t worry too much about gaining weight. Watch what you eat, take time for daily exercise, and change your eating habits if you need to. • Laughter helps. Watch or read something funny. Your body is now coming back into balance. During the ﬁ rst few days after you 3599255 NRO Gum UGuide_R1_V2 indd 27 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 18 After A Week Or Two. By now you should be feeling more conﬁ dent that you can handle those smoking urges. Many of your withdrawal symptoms have left by now, and you should be noticing some positive signs: less coughing, better breathing and an improved sense of taste and smell, to name a few. After A Month. You probably have the urge to smoke much less often now. But urges may still occur, and when they do, they are likely to be powerful ones that come out of nowhere. Don’t let them catch you off guard. Plan ahead for these difﬁ cult times. Concentrate on the ways non-smokers are more attractive than smokers. Their skin is less likely to wrinkle. Their teeth are whiter, cleaner. Their breath is fresher. Their hair and clothes smell better. That cough that seems to make even a laugh sound more like a rattle is a thing of the past. Their children and others around them are healthier, too. 3599255 NRO Gum UGuide_R1_V2 indd 28 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 19 What To Do About Relapse. What should you do if you slip and start smoking again? The answer is simple. A lapse of one or two or even a few cigarettes has not spoiled your efforts! Discard your cigarettes, forgive yourself and try again. If you start smoking again, keep your box of Nicorette Gum for your next quit attempt. If you have taken up regular smoking again, don’t be discouraged. Research shows that the best thing you can do is to try again. The important thing is to learn from your last attempt. • Admit that you’ve slipped, but don’t treat yourself as a failure. • Try to identify the “trigger” that caused you to slip, and prepare a better plan for dealing with this problem next time. • Talk positively to yourself – tell yourself that you have learned something from this experience. • Make sure you used Nicorette Gum correctly over the full 12 weeks to reduce your craving for nicotine. • Remember that it takes practice to do 3599255 NRO Gum UGuide_R1_V2 indd 29 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 20 anything, and quitting smoking is no exception. Once you’ve stopped smoking, take a second and pat yourself on your back. Now do it again. You deserve it. Remember now why you decided to stop smoking in the ﬁ rst place. Look at your list of reasons. Read them again. And smile. Now think about all the money you are saving and what you’ll do with it. All the non-smoking places you can go, and what you might do there. WHEN THE struggle IS over. All those years you may have added to your life, and what you’ll do with them. Remember that temptation may not be gone forever. However, the hard part is behind you so look forward with a positive attitude, and enjoy your new life as a non-smoker. QUESTIONS & ANSWERS. 1. How will I feel when I stop smoking and start using Nicorette Gum? You’ll need to prepare yourself for some nicotine withdrawal symptoms. These begin almost immediately after you stop 3599255 NRO Gum UGuide_R1_V2 indd 30 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 21 smoking, and are usually at their worst during the ﬁ rst three or four days. Understand that any of the following is possible: • craving for cigarettes • anxiety, irritability, restlessness, mood changes, nervousness • drowsiness • trouble concentrating • increased appetite and weight gain • headaches, muscular pain, constipation, fatigue. Nicorette Gum can help provide relief from withdrawal symptoms such as irritability and nervousness, as well as the craving for nicotine you used to satisfy by having a cigarette. 2. Is Nicorette Gum just substituting one form of nicotine for another? Nicorette Gum does contain nicotine. The purpose of Nicorette Gum is to provide you with enough nicotine to help control the physical withdrawal symptoms so you can deal with the mental aspects of quitting. Dur- ing the 12 week program, you will gradually 3599255 NRO Gum UGuide_R1_V2 indd 31 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 22 reduce your nicotine intake by switching to fewer pieces each day. 3. Can I be hurt by using Nicorette Gum? For most adults, the amount of nicotine in the gum is less than from smoking. Some people will be sensitive to even this amount of nicotine and should not use this product without advice from their doctor (see page 5). Because Nicorette Gum is a gum-based product, chewing it can cause dental ﬁ llings to loosen and aggravate other mouth, tooth and jaw problems. Nicorette Gum can also cause hiccups, heartburn and other stomach problems especially if chewed too quickly or not chewed correctly. 4. Will I gain weight? Many people do tend to gain a few pounds the ﬁ rst 8-10 weeks after they stop smok- ing. This is a very small price to pay for the enormous gains that you will make in your overall health and attractiveness. If you 3599255 NRO Gum UGuide_R1_V2 indd 32 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 23 continue to gain weight after the ﬁ rst two months, try to analyze what you’re doing differently. Reduce your fat intake, choose healthy snacks, and increase your physical activity to burn off the extra calories. 5. Is Nicorette Gum more expensive than smoking? The total cost of Nicorette Gum for the twelve week program is about equal to what a person who smokes one and a half packs of cigarettes a day would spend on cigarettes for the same period of time. Also, use of Nicorette Gum is only a short-term cost, while the cost of smoking is a long-term cost, because of the health problems smoking causes. 6. What if I slip up? Discard your cigarettes, forgive yourself and then get back on track. Don’t consider yourself a failure or punish yourself. In fact, people who have already tried to quit are more likely to be successful the next time. 3599255 NRO Gum UGuide_R1_V2 indd 33 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. My most important reasons to quit smoking are: WALLET CARD 3599255 NRO Gum UGuide_R1_V2 indd 35 4/18/13 12 01 PM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. keys to success. 1) You must really want to quit smoking for Nicorette® Gum to help you. 2) You can greatly increase your chances for success by using at least 9 to 12 pieces every day when you start using Nicorette Gum. See page 12. 3) You should continue to use Nicorette Gum as explained in this User’s Guide for 12 full weeks. If you feel you need to use Nicorette Gum for a longer period to keep from smoking, talk to your health care provider. 4) Nicorette Gum works best when used together with a support program — See page 3 for details. 5) If you have trouble using Nicorette Gum, ask your doctor or pharmacist or call GlaxoSmithKline at 1-800-419-4766 weekdays (10:00 am - 4:30 pm ET). 6) To request a free audio CD containing tips to help make quitting easier, call the toll free number listed above. (ONE CD PER CUSTOMER) 1 3599296 NRO GUM CS_UGuide_R1_V3 indd 3 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 2 SO YOU DECIDED TO QUIT. If you’ve tried to quit before and haven’t succeeded, don’t be discouraged! Quitting isn’t easy. It takes time, and most people try a few times before they are successful. The important thing is to try again until you succeed. This User’s Guide will give you support as you become a non-smoker. It will answer common questions about Nicorette Gum and give tips to help you stop smoking, and should be referred to often. Congratulations. Your decision to stop smoking is an important one. That’s why you’ve made the right choice in choosing Nicorette Gum. Your own chances of quitting smoking depend on how much you want to quit, how strongly you are addicted to tobacco, and how closely you follow a quitting program like the one that comes with Nicorette Gum. QuittinG Smoking is hard! 3599296 NRO GUM CS_UGuide_R1_V3 indd 4 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 3 If you ﬁ nd you cannot stop smoking or if you start smoking again after using Nicorette Gum, remember breaking this addiction doesn’t happen overnight. You may want to talk to a health care professional who can help you improve your chances of quitting the next time you try Nicorette Gum or another method. Your reason for quitting may be a combination of concerns about health, the effect of smoking on your appearance, and pressure from your family You are more likely to stop smoking by using Nicorette Gum with a support program that helps you break your smoking habit. There may be support groups in your area for people trying to quit. Call your local chapter of the American Lung Association, American Cancer Society or American Heart Association for further information. Toll free phone numbers are printed on the Wallet Card on the back cover of this User’s Guide. LET’S GET ORGaNIZED. where to get help. 3599296 NRO GUM CS_UGuide_R1_V3 indd 5 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. Smoking is addictive in two ways. Your need for nicotine has become both physical and mental. You must overcome both addictions to stop smoking. So while Nicorette Gum will lessen your body’s physical addiction to nicotine, you’ve got to want to quit smok- ing to overcome the mental dependence on cigarettes. Once you’ve decided that you’re going to quit, it’s time to get started. But ﬁ rst, there are some important warn- ings you should consider. and friends to stop smoking. Or maybe you’re concerned about the dangerous effect of second-hand smoke on the people you care about. All of these are good reasons. You probably have others. Decide your most important reasons, and write them down on the wallet card inside the back cover of this User’s Guide. Carry this card with you. In difﬁ cult moments, when you want to smoke, the card will remind you why you are quitting. WHAT YOU’RE UP AGAINST. 4 3599296 NRO GUM CS_UGuide_R1_V3 indd 6 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. This product is only for those who want to stop smoking. If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Some important WARNINGS. Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. • high blood pressure not controlled with medication. Nicotine can increase your blood pressure. • stomach ulcer or diabetes 5 3599296 NRO GUM CS_UGuide_R1_V3 indd 7 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 6 Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking a prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if • mouth, teeth or jaw problems occur • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat • oral blistering occurs • you have symptoms of an allergic reaction (such as difﬁ culty breathing or rash) Keep out of reach of children and pets. Pieces of nicotine gum may have enough nicotine to make children and pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. Becoming a non-smoker starts today. First, check that you bought the right starting dose. If you smoke your ﬁ rst cigarette within 30 minutes of waking up, use 4mg nicotine LET’S GET STARTED. 3599296 NRO GUM CS_UGuide_R1_V3 indd 8 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 7 gum. If you smoke your ﬁ rst cigarette more than 30 minutes after waking up, use 2mg nicotine gum. Next, read through the en- tire User’s Guide carefully. Then, set your personalized quitting schedule. Take out a calendar that you can use to track your progress, and identify four dates, using the stickers in the center of this User’s Guide: STEP 1. (Weeks 1-6). Your quit date (and the day you’ll start using Nicorette Gum). Choose your quit date (it should be soon). This is the day you will begin using Nicorette Gum to satisfy your cravings for nicotine. For the ﬁ rst six weeks, you’ll use a piece of Nicorette Gum every hour or two. Be sure to follow the directions starting on pages 10 and 12. Place the Step 1 stickers on this date. STEP 2. (Weeks 7 to 9). The day you’ll start reducing your use of Nicorette Gum. After six weeks, you’ll begin gradually reducing your Nicorette Gum usage to one piece every two to four hours. Place the Step 2 sticker on this date (the ﬁ rst day of week seven). 3599296 NRO GUM CS_UGuide_R1_V3 indd 9 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 8 STEP 3. (Weeks 10-12). The day you’ll further reduce your use of Nicorette Gum. Nine weeks after you begin using Nicorette Gum, you will further reduce your nicotine intake by using one piece every four to eight hours. Place the Step 3 sticker on this date (the ﬁ rst day of week ten). For the next three weeks, you’ll use a piece of Nicorette Gum every four to eight hours. End of treatment: The day you’ll complete Nicorette Gum therapy. Identify the date thirteen weeks after the date you chose in Step 1, and place the “EX-SMOKER” sticker on your calendar. Because smoking is an addiction, it is not easy to stop. After you’ve given up cigarettes, you will still have a strong urge to smoke. Plan ahead NOW for these times, so you’re not defeated in a moment of weakness. The following tips may help: • Keep the phone numbers of supportive friends and family members handy. • Keep a record of your quitting process. PLAN AHEAD. 3599296 NRO GUM CS_UGuide_R1_V3 indd 10 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 9 Track the number of Nicorette Gum pieces you use each day, and whether you feel a craving for cigarettes. In the event that you slip, immediately stop smoking and resume your quit attempt with the Nicorette Gum program. • Put together an Emergency Kit that includes items that will help take your mind off occasional urges to smoke. Include cinnamon gum or lemon drops to suck on, a relaxing CD, and something for your hands to play with, like a smooth rock, rubber band, or small metal balls. • Set aside some small rewards, like a new magazine or a gift certiﬁ cate from your favorite store, which you’ll “give” yourself after passing difﬁ cult hurdles. • Think now about the times when you most often want a cigarette, and then plan what else you might do instead of smoking. For instance, you might plan to take your coffee break in a new location, or take a walk right after dinner, so you won’t be tempted to smoke. 3599296 NRO GUM CS_UGuide_R1_V3 indd 11 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. the addictive part of cigarette smoke. Nicotine can cause side effects such as headache, nausea, upset stomach, and dizziness. If you are under 18 years of age, ask a doctor before use. Before you can use Nicorette Gum correctly, you have to prac- tice! That sounds silly, but it isn’t. Nicorette Gum isn’t like ordinary chewing gum. It’s a medicine, and must be chewed a certain way to work right. Chewed like ordinary gum, Nicorette Gum won’t work well and Nicorette Gum’s sug- ar-free chewing pieces provide nicotine to your system – they work as a temporary aid to help you quit smoking by reducing nicotine withdrawal symptoms. Nicorette Gum provides a lower level of nicotine to your blood than ciga- rettes, and allows you to gradually do away with your body’s need for nicotine. Because Nicorette Gum does not contain the tar or carbon monoxide of cigarette smoke, it does not have the same health dangers as tobacco. However, it still delivers nicotine, 10 HOW NICOrette gum works. HOW To Use NICOrette gum. 3599296 NRO GUM CS_UGuide_R1_V3 indd 12 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. can cause side effects. An overdose can occur if you chew more than one piece of Nicorette Gum at the same time, or if you chew many pieces one after another. Read all the following instructions before using Nicorette Gum. Refer to them often to make sure you’re using Nicorette Gum correctly. If you chew too fast, or do not chew correctly, you may get hiccups, heart- burn, or other stomach problems. Don’t eat or drink for 15 minutes before using Nicorette Gum, or while chewing a piece. The effectiveness of Nicorette Gum may be reduced by some foods and drinks, such as 11 coffee, juices, wine or soft drinks. 1) Begin using Nicorette Gum on your quit day. 2) To reduce craving and other withdrawal symptoms, use Nicorette Gum according to the dosage schedule on page 12. 3) Chew each Nicorette Gum piece very slowly several times. 4) Stop chewing when you notice a peppery taste, or a slight tingling in your mouth. (This usually happens after about 15 chews, but may vary from person to person.) 3599296 NRO GUM CS_UGuide_R1_V3 indd 13 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 12 5) “PARK” the Nicorette Gum piece between your cheek and gum, and leave it there. 6) When the peppery taste or tingle is almost gone (in about a minute), start to chew a few times slowly again. When the taste or tingle returns, stop again. 7) Park the Nicorette Gum piece again (in a different place in your mouth). 8) Repeat steps 3 to 7 (chew, chew, park) until most of the nicotine is gone from the Nicorette Gum piece (usually happens in about half an hour; the peppery taste or tingle won’t return.) 9) Wrap the used Nicorette Gum piece in paper and throw away in the trash. To improve your chances of quitting, use at least 9 pieces of Nicorette Gum a day. If you experience strong or frequent cravings, you may use a second piece within the hour. However, do not continuously use one The following chart lists the recommended usage schedule for Nicorette Gum: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 piece every 1 piece every 1 piece every 1 to 2 hours 2 to 4 hours 4 to 8 hours DO NOT USE MORE THAN 24 PIECES PER DAY. 3599296 NRO GUM CS_UGuide_R1_V3 indd 14 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHEN YOU CALL: You will be asked a few questions to understand YOU and YOUR speciﬁ c needs. AFTER YOU CALL: In a few days, you will receive your custom-tailored stop smoking plan. You will continue to receive personal, custom-tailored support — six times during the next twelve weeks. 3599296 NRO GUM CS_UGuide_R1_V3 indd 17 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How To Survive the First Week: Quitting Tips 3. Stay active. Keep busy to take your mind off smoking. 4. Think positive! The ﬁ rst week is the toughest. Remind yourself that it will get easier. Use the sample of the Stop Smoking Plan (see next page) to get you through the ﬁ rst week until your materials arrive. 1. Control your physical cravings for nicotine. Use enough – You can greatly increase your chances for success by using at least 9 to 12 pieces every day when you start using Nicorette Gum. 2. Get rid of all signs that you ever smoked — ashtrays, matches and, of course, cigarettes. 3599296 NRO GUM CS_UGuide_R1_V3 indd 20 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ©2013 GlaxoSmithKline The Committed Quitters ® program is a plan speciﬁ cally individualized for you. Call Between 7 am and 12 Midnight ET or enroll online 24 hours a day. (ONE PLAN PER CUSTOMER) NICORETTE and COMMITTED QUITTERS are registered trademarks, and associated logo designs and overall dress designs are trademarks owned and/or licensed to the GlaxoSmithKline group of companies. Read and follow label directions 3599296 NRO GUM CS_UGuide_R1_V3 indd 22 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 13 piece after another, since this may cause you hiccups, heartburn, nausea or other side effects. The goal of using Nicorette Gum is to slowly reduce your dependence on nico- tine. The schedule for using Nicorette Gum will help you reduce your nicotine craving gradually as you reduce and then stop your use of Nicorette Gum. Here are some tips to help you cut back during each step and then stop using Nicorette Gum: HOW to reduce your nicorette GUM usage. • After a while, start chewing each Nicorette Gum piece for only 10 to 15 minutes, instead of half an hour. Then, gradually begin to reduce the number of pieces used. • Or, try chewing each piece for longer than half an hour, but reduce the number of pieces you use each day. • Substitute ordinary chewing gum for some of the Nicorette Gum pieces you would normally use. Increase the number of pieces of ordinary gum as you cut back on the Nicorette Gum pieces. 3599296 NRO GUM CS_UGuide_R1_V3 indd 23 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 14 • Check how well you’ve reduced your daily usage of Nicorette Gum in Weeks 10 to 12. You should only be using about 3 to 5 pieces a day. Get ready to stop. The following tips may help you try to stop Nicorette Gum when you have completed treatment. • Set a stop date. • Use the same number of pieces of confectionery gum or mints as you were using Nicorette Gum per day. At the times when you have an urge to use Nicorette Gum, use a strong ﬂ avored gum or mint such as cinnamon or peppermint. • Reduce the number of pieces of gum or mints you use by one piece per day until you do not need to use any gum or mints. Talk to your doctor or health care provider if you: • still feel the need to use Nicorette Gum at the end of week 12 to keep from smoking • start using Nicorette Gum again after stopping • start smoking again 3599296 NRO GUM CS_UGuide_R1_V3 indd 24 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 15 Within the ﬁ rst few weeks of giving up smoking, you may be tempted to smoke for pleasure, particularly after completing a difﬁ cult task, or at a party or bar. Here are some tips to help get you through the important ﬁ rst stages of becoming a non-smoker: On Your Quit Date: • Ask your family, friends and co-workers to support you in your efforts to stop smoking. TIPS TO MAKE QUITTING EASIER. • Throw away all your cigarettes, matches, lighters, ashtrays, etc. • Keep busy on your quit day. Exercise. Go to a movie. Take a walk. Get together with friends. • Figure out how much money you’ll save by not smoking. Most ex-smokers can save more than $1,000 a year. • Write down what you will do with the money you save. 3599296 NRO GUM CS_UGuide_R1_V3 indd 25 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 16 • Know your high risk situations and plan ahead how you will deal with them. • Keep Nicorette Gum near your bed, so you’ll be prepared for any nicotine cravings when you wake up in the morning. • Visit your dentist and have your teeth cleaned to get rid of the tobacco stains. Right after Quitting: • During the ﬁ rst few days after you’ve stopped smoking, spend as much time as possible at places where smoking is not allowed. • Drink large quantities of water and fruit juices. • Try to avoid alcohol, coffee and other beverages you associate with smoking. • Remember that temporary urges to smoke will pass, even if you don’t smoke a cigarette. • Keep your hands busy with something like a pencil or a paper clip. • Find other activities which help you relax without cigarettes. • Swim, jog, take a walk, play basketball. 3599296 NRO GUM CS_UGuide_R1_V3 indd 26 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 17 stop smoking, you might feel edgy and nervous and have trouble concentrating. You might get headaches, feel dizzy and a little out of sorts, feel sweaty or have stomach upsets. You might even have trouble sleeping at ﬁ rst. These are typical withdrawal symptoms that will go away with time. Your smoker’s cough will get worse before it gets better. But don’t worry, that’s a good sign. Coughing helps clear the tar deposits out of your lungs. what to expect. • Don’t worry too much about gaining weight. Watch what you eat, take time for daily exercise, and change your eating habits if you need to. • Laughter helps. Watch or read something funny. Your body is now coming back into balance. During the ﬁ rst few days after you 3599296 NRO GUM CS_UGuide_R1_V3 indd 27 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 18 After A Week Or Two. By now you should be feeling more conﬁ dent that you can handle those smoking urges. Many of your withdrawal symptoms have left by now, and you should be noticing some positive signs: less coughing, better breathing and an improved sense of taste and smell, to name a few. After A Month. You probably have the urge to smoke much less often now. But urges may still occur, and when they do, they are likely to be powerful ones that come out of nowhere. Don’t let them catch you off guard. Plan ahead for these difﬁ cult times. Concentrate on the ways non-smokers are more attractive than smokers. Their skin is less likely to wrinkle. Their teeth are whiter, cleaner. Their breath is fresher. Their hair and clothes smell better. That cough that seems to make even a laugh sound more like a rattle is a thing of the past. Their children and others around them are healthier, too. 3599296 NRO GUM CS_UGuide_R1_V3 indd 28 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 19 What To Do About Relapse. What should you do if you slip and start smoking again? The answer is simple. A lapse of one or two or even a few cigarettes has not spoiled your efforts! Discard your cigarettes, forgive yourself and try again. If you start smoking again, keep your box of Nicorette Gum for your next quit attempt. If you have taken up regular smoking again, don’t be discouraged. Research shows that the best thing you can do is to try again. The important thing is to learn from your last attempt. • Admit that you’ve slipped, but don’t treat yourself as a failure. • Try to identify the “trigger” that caused you to slip, and prepare a better plan for dealing with this problem next time. • Talk positively to yourself – tell yourself that you have learned something from this experience. • Make sure you used Nicorette Gum correctly over the full 12 weeks to reduce your craving for nicotine. • Remember that it takes practice to do 3599296 NRO GUM CS_UGuide_R1_V3 indd 29 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 20 anything, and quitting smoking is no exception. Once you’ve stopped smoking, take a second and pat yourself on your back. Now do it again. You deserve it. Remember now why you decided to stop smoking in the ﬁ rst place. Look at your list of reasons. Read them again. And smile. Now think about all the money you are saving and what you’ll do with it. All the non-smoking places you can go, and what you might do there. WHEN THE struggle IS over. All those years you may have added to your life, and what you’ll do with them. Remember that temptation may not be gone forever. However, the hard part is behind you so look forward with a positive attitude, and enjoy your new life as a non-smoker. QUESTIONS & ANSWERS. 1. How will I feel when I stop smoking and start using Nicorette Gum? You’ll need to prepare yourself for some nicotine withdrawal symptoms. These begin almost immediately after you stop 3599296 NRO GUM CS_UGuide_R1_V3 indd 30 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 21 smoking, and are usually at their worst during the ﬁ rst three or four days. Understand that any of the following is possible: • craving for cigarettes • anxiety, irritability, restlessness, mood changes, nervousness • drowsiness • trouble concentrating • increased appetite and weight gain • headaches, muscular pain, constipation, fatigue. Nicorette Gum can help provide relief from withdrawal symptoms such as irritability and nervousness, as well as the craving for nicotine you used to satisfy by having a cigarette. 2. Is Nicorette Gum just substituting one form of nicotine for another? Nicorette Gum does contain nicotine. The purpose of Nicorette Gum is to provide you with enough nicotine to help control the physical withdrawal symptoms so you can deal with the mental aspects of quitting. Dur- ing the 12 week program, you will gradually 3599296 NRO GUM CS_UGuide_R1_V3 indd 31 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 22 reduce your nicotine intake by switching to fewer pieces each day. 3. Can I be hurt by using Nicorette Gum? For most adults, the amount of nicotine in the gum is less than from smoking. Some people will be sensitive to even this amount of nicotine and should not use this product without advice from their doctor (see page 5). Because Nicorette Gum is a gum-based product, chewing it can cause dental ﬁ llings to loosen and aggravate other mouth, tooth and jaw problems. Nicorette Gum can also cause hiccups, heartburn and other stomach problems especially if chewed too quickly or not chewed correctly. 4. Will I gain weight? Many people do tend to gain a few pounds the ﬁ rst 8-10 weeks after they stop smok- ing. This is a very small price to pay for the enormous gains that you will make in your overall health and attractiveness. If you 3599296 NRO GUM CS_UGuide_R1_V3 indd 32 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. 23 continue to gain weight after the ﬁ rst two months, try to analyze what you’re doing differently. Reduce your fat intake, choose healthy snacks, and increase your physical activity to burn off the extra calories. 5. Is Nicorette Gum more expensive than smoking? The total cost of Nicorette Gum for the twelve week program is about equal to what a person who smokes one and a half packs of cigarettes a day would spend on cigarettes for the same period of time. Also, use of Nicorette Gum is only a short-term cost, while the cost of smoking is a long-term cost, because of the health problems smoking causes. 6. What if I slip up? Discard your cigarettes, forgive yourself and then get back on track. Don’t consider yourself a failure or punish yourself. In fact, people who have already tried to quit are more likely to be successful the next time. 3599296 NRO GUM CS_UGuide_R1_V3 indd 33 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2013 GlaxoSmithKline Consumer Healthcare, L.P. My most important reasons to quit smoking are: WALLET CARD 3599296 NRO GUM CS_UGuide_R1_V3 indd 35 4/18/13 11 13 AM Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- MARIA E YSERN 10/28/2013 COLLEEN K ROGERS on behalf of RUTH E SCROGGS 10/28/2013 Reference ID: 3397578 Reference ID: 3398922 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:37.123334	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018612Orig1s068,020066Orig1s049lbl.pdf', 'application_number': 20066, 'submission_type': 'SUPPL ', 'submission_number': 49}
12,172	1 1 EC-NAPROSYN® (naproxen delayed-release tablets) 2 NAPROSYN® (naproxen tablets) 3 ANAPROX®/ANAPROX®DS (naproxen sodium tablets) 4 NAPROSYN®(naproxen suspension) 5 Rx only 6 7 8 9 DESCRIPTION 10 Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory 11 drugs. 12 The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2- 13 naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, sodium 14 salt, respectively. Naproxen and naproxen sodium have the following structures, 15 respectively: 16 17 Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. 18 Naproxen sodium has a molecular weight of 252.23 and a molecular formula of 19 C14H13NaO3. 20 Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, 21 practically insoluble in water at low pH and freely soluble in water at high pH. The 22 octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium 23 is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. 24 NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of 25 naproxen, peach tablets containing 375 mg of naproxen and yellow tablets containing 500 26 mg of naproxen for oral administration. The inactive ingredients are croscarmellose 27 sodium, iron oxides, povidone and magnesium stearate. 28 EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-coated white 29 tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration. 30 The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate. 31 The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, 32 sodium hydroxide and purified water. The dispersion may also contain simethicone 33 emulsion. The dissolution of this enteric-coated naproxen tablet is pH dependent with 34 rapid dissolution above pH 6. There is no dissolution below pH 4. 35 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 2 ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of 36 naproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue 37 tablets containing 550 mg of naproxen sodium for oral administration. The inactive 38 ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The 39 coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl 40 methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1- 41 4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain 42 hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or 43 Opadry YS-1-4216. 44 NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral 45 suspension containing 125 mg/5 mL of naproxen in a vehicle containing sucrose, 46 magnesium aluminum silicate, sorbitol solution and sodium chloride (30 mg/5 mL, 1.5 47 mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor, 48 imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to 49 3.7. 50 CLINICAL PHARMACOLOGY 51 Pharmacodynamics: Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with 52 analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a 53 more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism 54 of action of the naproxen anion, like that of other NSAIDs, is not completely understood 55 but may be related to prostaglandin synthetase inhibition. 56 Pharmacokinetics: Naproxen itself is rapidly and completely absorbed from the 57 gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms 58 of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak 59 concentration (Cmax); however, the products do differ in their pattern of absorption. These 60 differences between naproxen products are related to both the chemical form of naproxen 61 used and its formulation. Even with the observed differences in pattern of absorption, the 62 elimination half-life of naproxen is unchanged across products ranging from 12 to 17 63 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of 64 naproxen accumulation is consistent with this half-life. This suggests that the differences 65 in pattern of release play only a negligible role in the attainment of steady-state plasma 66 levels. 67 Absorption: 68 Immediate Release: After administration of NAPROSYN tablets, peak plasma levels are 69 attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are 70 attained in 1 to 2 hours. The difference in rates between the two products is due to the 71 increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak 72 plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. 73 Delayed Release: EC-NAPROSYN is designed with a pH-sensitive coating to provide a 74 barrier to disintegration in the acidic environment of the stomach and to lose integrity in 75 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 3 the more neutral environment of the small intestine. The enteric polymer coating selected 76 for EC-NAPROSYN dissolves above pH 6. When EC-NAPROSYN was given to fasted 77 subjects, peak plasma levels were attained about 4 to 6 hours following the first dose 78 (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN 79 tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine 80 rather than the stomach, so the absorption of the drug is delayed until the stomach is 81 emptied. 82 When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a 83 crossover study following 1 week of dosing, differences in time to peak plasma levels 84 (Tmax) were observed, but there were no differences in total absorption as measured by 85 Cmax and AUC: 86 EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61%) AUC0–12 hr (µg·hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) 87 Antacid Effects: When EC-NAPROSYN was given as a single dose with antacid (54 mEq 88 buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to 89 peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although 90 not significantly. 91 Food Effects: When EC-NAPROSYN was given as a single dose with food, peak plasma 92 levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence 93 time in the small intestine until disintegration was independent of food intake. The 94 presence of food prolonged the time the tablets remained in the stomach, time to first 95 detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did 96 not affect peak naproxen levels (Cmax). 97 Distribution: 98 Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is 99 greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is 100 less than proportional increase in plasma levels due to an increase in clearance caused by 101 saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 102 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen). The naproxen anion 103 has been found in the milk of lactating women at a concentrations equivalent to 104 approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS: 105 Nursing Mothers). 106 Metabolism: 107 Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and 108 metabolites do not induce metabolizing enzymes. 109 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 4 Excretion: 110 The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from 111 any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl 112 naproxen (less than 1%) or their conjugates (66% to 92%). The plasma half-life of the 113 naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of 114 both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of 115 excretion have been found to coincide closely with the rate of naproxen disappearance 116 from the plasma. In patients with renal failure metabolites may accumulate (see 117 PRECAUTIONS: Renal Effects). 118 Special Populations: 119 Pediatric Patients: In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen 120 levels following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND 121 ADMINISTRATION) were found to be similar to those found in normal adults following 122 a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. 123 Pharmacokinetic studies of naproxen were not performed in pediatric patients younger 124 than 5 years of age. Pharmacokinetic parameters appear to be similar following 125 administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN 126 has not been studied in subjects under the age of 18. 127 Geriatric Patients: Studies indicate that although total plasma concentration of naproxen 128 is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, 129 although the unbound fraction is less than 1% of the total naproxen concentration. 130 Unbound trough naproxen concentrations in elderly subjects have been reported to range 131 from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% 132 in younger subjects. The clinical significance of this finding is unclear, although it is 133 possible that the increase in free naproxen concentration could be associated with an 134 increase in the rate of adverse events per a given dosage in some elderly patients. 135 Race: Pharmacokinetic differences due to race have not been studied. 136 Hepatic Insufficiency: Naproxen pharmacokinetics has not been determined in subjects 137 with hepatic insufficiency. 138 Renal Insufficiency: Naproxen pharmacokinetics has not been determined in subjects 139 with renal insufficiency. Given that naproxen, its metabolites and conjugates are 140 primarily excreted by the kidney, the potential exists for naproxen metabolites to 141 accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased 142 in patients with severe renal impairment. Naproxen-containing products are not 143 recommended for use in patients with moderate to severe and severe renal impairment 144 (creatinine < 30 ml/min) (see PRECAUTIONS: Renal Effects). 145 CLINICAL STUDIES 146 General Information: Naproxen has been studied in patients with rheumatoid arthritis, 147 osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute 148 gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a 149 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 5 reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in 150 disease activity as assessed by both the investigator and patient, and by increased 151 mobility as demonstrated by a reduction in walking time. Generally, response to 152 naproxen has not been found to be dependent on age, sex, severity or duration of 153 rheumatoid arthritis. 154 In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a 155 reduction in joint pain or tenderness, an increase in range of motion in knee joints, 156 increased mobility as demonstrated by a reduction in walking time, and improvement in 157 capacity to perform activities of daily living impaired by the disease. 158 In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a 159 day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated 160 prematurely because of adverse events. Nineteen patients in the 1500 mg group 161 terminated prematurely because of adverse events. Most of these adverse events were 162 gastrointestinal events. 163 In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile 164 arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in 165 controlling the aforementioned measures of disease activity, but the frequency and 166 severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and 167 nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in 168 naproxen-treated patients than in those treated with aspirin or indomethacin. 169 In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, 170 morning stiffness and pain at rest. In double-blind studies the drug was shown to be as 171 effective as aspirin, but with fewer side effects. 172 In patients with acute gout, a favorable response to naproxen was shown by significant 173 clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, 174 as well as by relief of pain and tenderness. 175 Naproxen has been studied in patients with mild to moderate pain secondary to 176 postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and 177 dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen 178 and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown 179 by such measures as reduction of pain intensity scores, increase in pain relief scores, 180 decrease in numbers of patients requiring additional analgesic medication, and delay in 181 time to remedication. The analgesic effect has been found to last for up to 12 hours. 182 Naproxen may be used safely in combination with gold salts and/or corticosteroids; 183 however, in controlled clinical trials, when added to the regimen of patients receiving 184 corticosteroids, it did not appear to cause greater improvement over that seen with 185 corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been 186 adequately studied. When added to the regimen of patients receiving gold salts, naproxen 187 did result in greater improvement. Its use in combination with salicylates is not 188 recommended because there is evidence that aspirin increases the rate of excretion of 189 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 6 naproxen and data are inadequate to demonstrate that naproxen and aspirin produce 190 greater improvement over that achieved with aspirin alone. In addition, as with other 191 NSAIDs, the combination may result in higher frequency of adverse events than 192 demonstrated for either product alone. 193 In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 194 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX 195 (naproxen sodium) has been demonstrated to cause statistically significantly less gastric 196 bleeding and erosion than 3250 mg of aspirin. 197 Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 198 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted 199 comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and 200 osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These 201 studies indicated that EC-NAPROSYN and NAPROSYN showed no significant 202 differences in efficacy or safety and had similar prevalence of minor GI complaints. 203 Individual patients, however, may find one formulation preferable to the other. 204 Five hundred and fifty-three patients received EC-NAPROSYN during long-term open- 205 label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed 206 peptic ulcers and GI bleeds were similar to what has been historically reported for long- 207 term NSAID use. 208 Geriatric Patients: The hepatic and renal tolerability of long-term naproxen 209 administration was studied in two double blind clinical trials involving 586 patients. Of 210 the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 211 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice 212 daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and 213 renal function were noted in some patients, although there were no differences noted in 214 the occurrence of abnormal values among different age groups. 215 INDIVIDUALIZATION OF DOSAGE 216 Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and 217 ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic 218 differences that may affect onset of action. Onset of pain relief can begin within 30 219 minutes in patients taking naproxen sodium and within 1 hour in patients taking 220 naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the 221 stomach, the absorption of the drug is delayed compared to the other naproxen 222 formulations (see CLINICAL PHARMACOLOGY). 223 The recommended strategy for initiating therapy is to choose a formulation and a starting 224 dose likely to be effective for the patient and then adjust the dosage based on observation 225 of benefit and/or adverse events. A lower dose should be considered in patients with renal 226 or hepatic impairment or in elderly patients (see PRECAUTIONS). 227 Analgesia/Dysmenorrhea/Bursitis and Tendinitis: Because the sodium salt of naproxen 228 is more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the 229 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 7 management of acute painful conditions when prompt onset of pain relief is desired. The 230 recommended starting dose is 550 mg followed by 550 mg every 12 hours or 275 mg 231 every 6 to 8 hours, as required. The initial total daily dose should not exceed 1375 mg of 232 naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen 233 sodium. NAPROSYN may also be used for treatment of acute pain and dysmenorrhea. 234 EC-NAPROSYN is not recommended for initial treatment of acute pain because 235 absorption of naproxen is delayed compared to other naproxen-containing products (see 236 CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). 237 Acute Gout: The recommended starting dose is 750 mg of NAPROSYN followed by 250 238 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting 239 dose of 825 mg followed by 275 mg every 8 hours as needed. EC-NAPROSYN is not 240 recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). 241 Osteoarthritis/Rheumatoid Arthritis/Ankylosing Spondylitis: The recommended dose of 242 naproxen is NAPROSYN or NAPROSYN Suspension 250 mg, 375 mg or 500 mg taken 243 twice daily (morning and evening) or EC-NAPROSYN 375 mg or 500 mg taken twice 244 daily. Naproxen sodium may also be used (see DOSAGE AND ADMINISTRATION). 245 During long-term administration the dose of naproxen may be adjusted up or down 246 depending on the clinical response of the patient. A lower daily dose may suffice for 247 long-term administration. In patients who tolerate lower doses well, the dose may be 248 increased to 1500 mg per day for up to 6 months when a higher level of anti- 249 inflammatory/analgesic activity is required. When treating patients with naproxen 1500 250 mg/day (as NAPROSYN or 1650 mg of ANAPROX), the physician should observe 251 sufficient increased clinical benefit to offset the potential increased risk. The morning and 252 evening doses do not have to be equal in size and administration of the drug more 253 frequently than twice daily does not generally make a difference in response (see 254 CLINICAL PHARMACOLOGY). 255 Juvenile Arthritis: The use of NAPROSYN Suspension allows for more flexible dose 256 titration. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen 257 similar to those seen in adults taking 500 mg of naproxen (see CLINICAL 258 PHARMACOLOGY). 259 The recommended total daily dose is approximately 10 mg/kg given in two divided doses 260 (ie, 5 mg/kg given twice a day) (see DOSAGE AND ADMINISTRATION). 261 INDICATIONS AND USAGE 262 Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 263 NAPROSYN Suspension is indicated: 264 • For the relief of the signs and symptoms of rheumatoid arthritis 265 • For the relief of the signs and symptoms of osteoarthritis 266 • For the relief of the signs and symptoms of ankylosing spondylitis 267 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 8 • For the relief of the signs and symptoms of juvenile arthritis 268 Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis 269 in order to obtain the maximum dosage flexibility based on the patient’s weight. 270 Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is 271 also indicated: 272 • For relief of the signs and symptoms of tendinitis 273 • For relief of the signs and symptoms of bursitis 274 • For relief of the signs and symptoms of acute gout 275 • For the management of pain 276 • For the management of primary dysmenorrhea 277 EC-NAPROSYN is not recommended for initial treatment of acute pain because the 278 absorption of naproxen is delayed compared to absorption from other naproxen- 279 containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND 280 ADMINISTRATION). 281 CONTRAINDICATIONS 282 All naproxen products are contraindicated in patients who have had allergic reactions to 283 prescription as well as to over-the-counter products containing naproxen. It is also 284 contraindicated in patients in whom aspirin or other nonsteroidal anti- 285 inflammatory/analgesic drugs induce the syndrome of asthma, rhinitis, and nasal polyps. 286 Both types of reactions have the potential of being fatal. Anaphylactoid reactions to 287 naproxen, whether of the true allergic type or the pharmacologic idiosyncratic (eg, aspirin 288 hypersensitivity syndrome) type, usually but not always occur in patients with a known 289 history of such reactions. Therefore, careful questioning of patients for such things as 290 asthma, nasal polyps, urticaria, and hypotension associated with nonsteroidal anti- 291 inflammatory drugs before starting therapy is important. In addition, if such symptoms 292 occur during therapy, treatment should be discontinued (see WARNINGS: Anaphylactoid 293 Reactions and PRECAUTIONS: Preexisting Asthma). 294 WARNINGS 295 Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation: 296 Serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the 297 stomach, small intestine or large intestine, can occur at any time, with or without warning 298 symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). 299 Minor upper gastrointestinal problems, such as dyspepsia, are common and may also 300 occur at any time during NSAID therapy. Therefore, physicians and patients should 301 remain alert for ulceration and bleeding, even in the absence of previous GI tract 302 symptoms (see PRECAUTIONS: Hematological Effects). Patients should be informed 303 about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. 304 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 9 The utility of periodic laboratory monitoring has not been demonstrated, nor has it been 305 adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event 306 on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross 307 bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of 308 patients treated for 3 to 6 months and in about 2% to 4% of patients treated for 1 year. 309 These trends continue, thus increasing the likelihood of developing a serious GI event at 310 some time during the course of therapy. However, even short-term therapy is not without 311 risk. 312 NSAIDs should be prescribed with extreme caution in patients with a prior history of 313 ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are 314 in elderly or debilitated patients and therefore special care should be taken in treating this 315 population. To minimize the potential risk for an adverse GI event, the lowest 316 effective dose should be used for the shortest possible duration. For high-risk patients, 317 alternate therapies that do not involve NSAIDs should be considered. 318 Studies have shown that patients with a prior history of peptic ulcer disease and/or 319 gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for 320 developing a GI bleed than patients with neither of these risk factors. In addition to a past 321 history of ulcer disease, pharmacoepidemiological studies have identified several other 322 co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: 323 treatment with oral corticosteroids, treatment with anticoagulants, longer duration of 324 NSAID therapy, smoking, alcoholism, older age, and poor general health status. 325 Anaphylactoid Reactions: As with other NSAIDs, anaphylactoid reactions may occur in 326 patients without known prior exposure to naproxen. Naproxen should not be given to 327 patients with the aspirin triad. This symptom complex typically occurs in asthmatic 328 patients who experience rhinitis with or without nasal polyps, or who exhibit severe, 329 potentially fatal bronchospasm after taking aspirin or other NSAIDs (see 330 CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help 331 should be sought in cases where an anaphylactoid reaction occurs. 332 Advanced Renal Disease: In cases with advanced kidney disease, treatment with 333 naproxen is not recommended. If NSAID therapy, however, must be initiated, close 334 monitoring of the patient’s kidney function is advisable (see PRECAUTIONS: Renal 335 Effects). 336 Pregnancy: In late pregnancy, as with other NSAIDs, naproxen should be avoided 337 because it may cause premature closure of the ductus arteriosus. 338 PRECAUTIONS 339 General: NAPROXEN-CONTAINING PRODUCTS SUCH AS NAPROSYN, EC- 340 NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, 341 AND OTHER NAPROXEN PRODUCTS SHOULD NOT BE USED 342 CONCOMITANTLY SINCE THEY ALL CIRCULATE IN THE PLASMA AS 343 THE NAPROXEN ANION. 344 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 10 Naproxen cannot be expected to substitute for corticosteroids or to treat corticosteroid 345 insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. 346 Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a 347 decision is made to discontinue corticosteroids and the patient should be observed closely 348 for any evidence of adverse effects, including adrenal insufficiency and exacerbation of 349 symptoms of arthritis. 350 Patients with initial hemoglobin values of 10 g or less who are to receive long-term 351 therapy should have hemoglobin values determined periodically. 352 The antipyretic and anti-inflammatory activities of the drug may reduce fever and 353 inflammation, thus diminishing their utility as diagnostic signs in detecting complications 354 of presumed noninfectious, noninflammatory painful conditions. 355 Because of adverse eye findings in animal studies with drugs of this class, it is 356 recommended that ophthalmic studies be carried out if any change or disturbance in 357 vision occurs. 358 Hepatic Effects: As with other nonsteroidal anti-inflammatory drugs, borderline 359 elevations of one or more liver tests may occur in up to 15% of patients. These 360 abnormalities may progress, may remain essentially unchanged, or may be transient with 361 continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver 362 dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or 363 SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. A patient 364 with symptoms and/or signs suggesting liver dysfunction or in whom an abnormal liver 365 test has occurred, should be evaluated for evidence of the development of more severe 366 hepatic reaction while on therapy with naproxen. Severe hepatic reactions, including 367 jaundice and cases of fatal hepatitis, have been reported with naproxen as with other 368 nonsteroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver 369 tests persist or worsen, if clinical signs and symptoms consistent with liver disease 370 develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), naproxen 371 should be discontinued. 372 Renal Effects: Caution should be used when initiating treatment with naproxen in 373 patients with considerable dehydration. It is advisable to rehydrate patients first and then 374 start therapy with naproxen. Caution is also recommended in patients with pre-existing 375 kidney disease (see WARNINGS: Advanced Renal Disease). 376 As with other nonsteroidal anti-inflammatory drugs, long-term administration of 377 naproxen to animals has resulted in renal papillary necrosis and other abnormal renal 378 pathology. In humans, there have been reports of impaired renal function, renal failure, 379 acute interstitial nephritis, hematuria, proteinuria, renal papillary necrosis, and 380 occasionally nephrotic syndrome associated with naproxen-containing products and other 381 NSAIDs since they have been marketed. 382 A second form of renal toxicity has been seen in patients taking naproxen as well as other 383 nonsteroidal anti-inflammatory drugs. In patients with prerenal conditions leading to a 384 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 11 reduction in renal blood flow or blood volume, where the renal prostaglandins have a 385 supportive role in the maintenance of renal perfusion, caution should be observed since 386 administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent 387 reduction in prostaglandin formation and may precipitate overt renal decompensation or 388 failure. Patients at greatest risk of this reaction are those with impaired renal function, 389 hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and 390 ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory 391 therapy is typically followed by recovery to the pretreatment state. 392 Naproxen and its metabolites are eliminated primarily by the kidneys; therefore, the drug 393 should be used with caution in such patients and the monitoring of serum creatinine 394 and/or creatinine clearance is advised. A reduction in daily dosage should be considered 395 to avoid the possibility of excessive accumulation of naproxen metabolites in these 396 patients. Naproxen-containing products are not recommended for use in patients with 397 moderate to severe and severe renal impairment (creatinine < 30 ml/min). 398 Chronic alcoholic liver disease and probably other diseases with decreased or abnormal 399 plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the 400 plasma concentration of unbound naproxen is increased. Caution is advised when high 401 doses are required and some adjustment of dosage may be required in these patients. It is 402 prudent to use the lowest effective dose. 403 Studies indicate that although total plasma concentration of naproxen is unchanged, the 404 unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when 405 high doses are required and some adjustment of dosage may be required in elderly 406 patients. As with other drugs used in the elderly, it is prudent to use the lowest effective 407 dose. 408 Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, 409 including naproxen. This may be due to fluid retention, GI loss, or an incompletely 410 described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, 411 including naproxen, should have their hemoglobin or hematocrit checked if they exhibit 412 any signs or symptoms of anemia. 413 All drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent 414 with platelet function and vascular responses to bleeding. 415 NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in 416 some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of 417 shorter duration, and reversible. Naproxen does not generally affect platelet counts, 418 prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving naproxen 419 who may be adversely affected by alterations in platelet function, such as those with 420 coagulation disorders or patients receiving anticoagulants, should be carefully monitored. 421 Fluid Retention and Edema: Peripheral edema has been observed in some patients 422 receiving naproxen. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 423 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of 424 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 12 NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen) 425 of sodium, this should be considered in patients whose overall intake of sodium must be 426 severely restricted. For these reasons, ANAPROX, ANAPROX DS and NAPROSYN 427 Suspension should be used with caution in patients with fluid retention, hypertension or 428 heart failure. 429 Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of 430 aspirin in patients with aspirin-sensitive asthma has been associated with severe 431 bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, 432 between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such 433 aspirin-sensitive patients, naproxen should not be administered to patients with this form 434 of aspirin sensitivity and should be used with caution in patients with preexisting asthma. 435 Information for Patients: Naproxen, in NAPROSYN, EC-NAPROSYN, ANAPROX, 436 ANAPROX DS and NAPROSYN Suspension can cause discomfort and, rarely, more 437 serious side effects, such as gastrointestinal bleeding, which may result in hospitalization 438 and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur 439 without warning symptoms, patients should be alert for the signs and symptoms of 440 ulcerations and bleeding, and should ask for medical advice when observing any 441 indicative signs or symptoms. Patients should be apprised of the importance of this 442 follow-up (see WARNINGS: Gastrointestinal (GI) Effects-Risk of GI Ulceration, 443 Bleeding, and Perforation). 444 Patients should promptly report signs or symptoms of gastrointestinal ulceration or 445 bleeding, skin rash, unexplained weight gain or edema to their physicians. 446 Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, 447 nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu- 448 like” symptoms). If these occur, patients should be instructed to stop therapy and seek 449 immediate medical therapy. 450 Patients should also be instructed to seek immediate emergency help in the case of an 451 anaphylactoid reaction (see WARNINGS). 452 In late pregnancy, naproxen, in NAPROSYN, EC-NAPROSYN, ANAPROX, 453 ANAPROX DS, and NAPROSYN SUSPENSION, should be avoided because it may 454 cause premature closure of the ductus arteriosus. 455 Caution should be exercised by patients whose activities require alertness if they 456 experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. 457 Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without 458 warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. If 459 clinical signs and symptoms consistent with liver or renal disease develop, systemic 460 manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or 461 worsen, naproxen should be discontinued. 462 Drug Interactions: 463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 13 Aspirin: Concomitant administration of naproxen and aspirin is not recommended 464 because naproxen is displaced from its binding sites during the concomitant 465 administration of aspirin, resulting in lower plasma concentrations and peak plasma 466 levels. 467 Methotrexate: Caution should be used if naproxen is administered concomitantly with 468 methotrexate. Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory 469 drugs have been reported to reduce the tubular secretion of methotrexate in an animal 470 model, possibly increasing the toxicity of methotrexate. 471 ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect 472 of ACE-inhibitors. The use of NSAIDs in patients who are receiving ACE inhibitors may 473 potentiate renal disease states (see PRECAUTIONS: Renal Effects). 474 Furosemide: Clinical studies, as well as postmarketing observations, have shown that 475 NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. 476 This response has been attributed to inhibition of renal prostaglandin synthesis. 477 Lithium: Inhibition of renal lithium clearance leading to increases in plasma lithium 478 concentrations has also been reported. The mean minimum lithium concentration 479 increased 15% and the renal clearance was decreased by approximately 20%. These 480 effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. 481 Thus, when NSAIDs and lithium are administered concurrently, patients should be 482 observed carefully for signs of lithium toxicity. 483 Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that 484 patients taking both drugs have a risk of serious GI bleeding that is higher than patients 485 taking either drug alone. No significant interactions have been observed in clinical 486 studies with naproxen and coumarin-type anticoagulants. However, caution is advised 487 since interactions have been seen with other nonsteroidal agents of this class. The free 488 fraction of warfarin may increase substantially in some subjects and naproxen interferes 489 with platelet function. 490 Other Information Concerning Drug Interactions: 491 Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for 492 interaction with other albumin-bound drugs such as coumarin-type anticoagulants, 493 sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously 494 receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed 495 for adjustment of dose if required. 496 Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the 497 antihypertensive effect of propranolol and other beta-blockers. 498 Probenecid given concurrently increases naproxen anion plasma levels and extends its 499 plasma half-life significantly. 500 Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid 501 therapy, concomitant administration of EC-NAPROSYN is not recommended. 502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 14 Drug/Laboratory Test Interactions: Naproxen may decrease platelet aggregation and 503 prolong bleeding time. This effect should be kept in mind when bleeding times are 504 determined. 505 The administration of naproxen may result in increased urinary values for 17-ketogenic 506 steroids because of an interaction between the drug and/or its metabolites with m-di- 507 nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements 508 (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy 509 with naproxen be temporarily discontinued 72 hours before adrenal function tests are 510 performed if the Porter-Silber test is to be used. 511 Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid 512 (5HIAA). 513 Carcinogenesis: A 2-year study was performed in rats to evaluate the carcinogenic 514 potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). 515 The maximum dose used was 0.28 times the systemic exposure to humans at the 516 recommended dose. No evidence of tumorigenicity was found. 517 Pregnancy: Teratogenic Effects: Pregnancy Category C. Reproduction studies have been 518 performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic 519 exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic 520 exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic 521 exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. 522 There are no adequate and well-controlled studies in pregnant women. Because animal 523 reproduction studies are not always predictive of human response, naproxen should not 524 be used during pregnancy unless clearly needed. 525 Nonteratogenic Effects: There is some evidence to suggest that when inhibitors of 526 prostaglandin synthesis are used to delay preterm labor there is an increased risk of 527 neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and 528 intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition 529 has been associated with persistent pulmonary hypertension, renal dysfunction and 530 abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs 531 of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use 532 during third trimester should be avoided. 533 Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit 534 prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and 535 decreased pup survival occurred. Naproxen-containing products are not recommended in 536 labor and delivery because, through its prostaglandin synthesis inhibitory effect, 537 naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus 538 increasing the risk of uterine hemorrhage. 539 Nursing Mothers: The naproxen anion has been found in the milk of lactating women at 540 a concentrations equivalent to approximately 1% of maximum naproxen concentration in 541 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 15 plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on 542 neonates, use in nursing mothers should be avoided. 543 Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 years 544 have not been established. Pediatric dosing recommendations for juvenile arthritis are 545 based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are 546 no adequate effectiveness or dose-response data for other pediatric conditions, but the 547 experience in juvenile arthritis and other use experience have established that single 548 doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND 549 ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well 550 tolerated in pediatric patients over 2 years of age. 551 Geriatric Use: Studies indicate that although total plasma concentration of naproxen is 552 unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution 553 is advised when high doses are required and some adjustment of dosage may be required 554 in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest 555 effective dose. 556 Experience indicates that geriatric patients may be particularly sensitive to certain 557 adverse effects of nonsteroidal anti-inflammatory drugs. While age does not appear to be 558 an independent risk factor for the development of peptic ulceration and bleeding with 559 naproxen administration, elderly or debilitated patients seem to tolerate peptic ulceration 560 or bleeding less well when these events do occur. Most spontaneous reports of fatal GI 561 events are in the geriatric population (see WARNINGS). 562 Naproxen is known to be substantially excreted by the kidney, and the risk of toxic 563 reactions to this drug may be greater in patients with impaired renal function. Because 564 elderly patients are more likely to have decreased renal function, care should be taken in 565 dose selection, and it may be useful to monitor renal function. Geriatric patients may be 566 at a greater risk for the development of a form of renal toxicity precipitated by reduced 567 prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs 568 (see PRECAUTIONS: Renal Effects). 569 ADVERSE REACTIONS 570 Adverse reactions reported in controlled clinical trials in 960 patients treated for 571 rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients 572 treated chronically were reported 2 to 10 times more frequently than they were in short- 573 term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. 574 The most frequent complaints reported related to the gastrointestinal tract. 575 A clinical study found gastrointestinal reactions to be more frequent and more severe in 576 rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those 577 taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). 578 In controlled clinical trials with about 80 pediatric patients and in well-monitored, open- 579 label studies with about 400 pediatric patients with juvenile arthritis treated with 580 naproxen, the incidence of rash and prolonged bleeding times were increased, the 581 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 16 incidence of gastrointestinal and central nervous system reactions were about the same, 582 and the incidence of other reactions were lower in pediatric patients than in adults. 583 In patients taking naproxen in clinical trials, the most frequently reported adverse 584 experiences in approximately 1 to 10% of patients are: 585 Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, 586 constipation, diarrhea, dyspepsia, stomatitis 587 Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo 588 Dermatologic: pruritus (itching) , skin eruptions, ecchymoses, sweating, purpura 589 Special Senses: tinnitus, visual disturbances, hearing disturbances 590 Cardiovascular: edema, palpitations 591 General: dyspnea, thirst 592 Incidence of reported reaction between 3% and 9%. Those reactions occurring in less 593 than 3% of the patients are unmarked. 594 In patients taking NSAIDs, the following adverse experiences have also been reported in 595 approximately 1 to 10% of patients. 596 Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI 597 ulcers (gastric/duodenal), vomiting 598 General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding 599 time, rashes 600 The following are additional adverse experiences reported in <1% of patients taking 601 naproxen during clinical trials and through post-marketing reports. Those adverse 602 reactions observed through post-marketing reports are italicized. 603 Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, 604 pyrexia (chills and fever) 605 Cardiovascular: congestive heart failure, vasculitis 606 Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, 607 pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal 608 ulceration, ulcerative stomatitis 609 Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, 610 agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia 611 Metabolic and Nutritional: hyperglycemia, hypoglycemia 612 Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, 613 malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction 614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 17 Respiratory: eosinophilic pneumonitis 615 Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema 616 multiforme, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity 617 reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) 618 or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of 619 pseudoporphyria occur, treatment should be discontinued and the patient monitored. 620 Special Senses: hearing impairment 621 Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, 622 nephrotic syndrome, renal disease, renal failure, renal papillary necrosis 623 In patients taking NSAIDs, the following adverse experiences have also been reported in 624 <1% of patients. 625 Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death 626 Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, 627 myocardial infarction 628 Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, 629 hepatitis, eructation, liver failure 630 Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia 631 Metabolic and Nutritional: weight changes 632 Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, 633 tremors, convulsions, coma, hallucinations 634 Respiratory: asthma, respiratory depression, pneumonia 635 Dermatologic: exfoliative dermatitis 636 Special Senses: blurred vision, conjunctivitis 637 Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 638 OVERDOSAGE 639 Significant naproxen overdosage may be characterized by lethargy, dizziness, 640 drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, 641 transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic 642 acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. 643 Hypertension, acute renal failure, respiratory depression, and coma may occur, but are 644 rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, 645 and may occur following an overdose. Because naproxen sodium may be rapidly 646 absorbed, high and early blood levels should be anticipated. A few patients have 647 experienced convulsions, but it is not clear whether or not these were drug-related. It is 648 not known what dose of the drug would be life threatening. The oral LD50 of the drug is 649 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 18 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 650 mg/kg in dogs. 651 Patients should be managed by symptomatic and supportive care following a NSAID 652 overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma 653 concentration of naproxen because of the high degree of its protein binding. Emesis 654 and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic 655 cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or 656 following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may 657 not be useful due to high protein binding. 658 DOSAGE AND ADMINISTRATION 659 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis: 660 NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be 661 broken, crushed or chewed during ingestion. 662 During long-term administration, the dose of naproxen may be adjusted up or down 663 depending on the clinical response of the patient. A lower daily dose may suffice for 664 long-term administration. The morning and evening doses do not have to be equal in size 665 and the administration of the drug more frequently than twice daily is not necessary. 666 In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 667 mg per day for limited periods of up to 6 months when a higher level of anti- 668 inflammatory/analgesic activity is required. When treating such patients with naproxen 669 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset 670 the potential increased risk (see CLINICAL PHARMACOLOGY and 671 INDIVIDUALIZATION OF DOSAGE). 672 Geriatric Patients: Studies indicate that although total plasma concentration of naproxen 673 is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. 674 Caution is advised when high doses are required and some adjustment of dosage may be 675 required in elderly patients. As with other drugs used in the elderly, it is prudent to use 676 the lowest effective dose. 677 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 19 Juvenile Arthritis: The recommended total daily dose of naproxen is approximately 10 678 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked 679 in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN 680 Suspension. The following table may be used as a guide for dosing of NAPROSYN 681 Suspension: 682 Patient’s Weight Dose Administered as 683 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 684 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 685 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily 686 Management of Pain, Primary Dysmenorrhea and Acute Tendonitis and Bursitis: The 687 recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX 688 DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The 689 initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the 690 total daily dose should not exceed 1100 mg of naproxen sodium. NAPROSYN may also 691 be used but EC-NAPROSYN is not recommended for initial treatment of acute pain 692 because absorption of naproxen is delayed compared to other naproxen-containing 693 products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE and 694 INDIVIDUALIZATION OF DOSAGE). 695 Acute Gout: The recommended starting dose is 750 mg of NAPROSYN followed by 250 696 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting 697 dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not 698 recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). 699 HOW SUPPLIED 700 NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on 701 one side and scored on the other. Packaged in light-resistant bottles of 100. 702 100’s (bottle): NDC 0004-6313-01. 703 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light- 704 resistant bottles of 100 and 500. 705 100’s (bottle): NDC 0004-6314-01; 500’s (bottle): NDC 0004-6314-14. 706 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on 707 the other. Packaged in light-resistant bottles of 100 and 500. 708 100’s (bottle): NDC 0004-6316-01; 500’s (bottle): NDC 0004-6316-14. 709 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant 710 containers. 711 NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 712 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28). 713 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 20 Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense 714 in light-resistant containers. 715 EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, capsule-shaped, imprinted 716 with EC-NAPROSYN on one side and 375 on the other. Packaged in light-resistant 717 bottles of 100. 718 100’s (bottle): NDC 0004-6415-01. 719 500 mg: white, capsule-shaped, imprinted with EC-NAPROSYN on one side and 500 on 720 the other. Packaged in light-resistant bottles of 100. 721 100’s (bottle): NDC 0004-6416-01. 722 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant 723 containers. 724 ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with 725 NPS-275 on one side. Packaged in bottles of 100. 726 100’s (bottle): NDC 0004-6202-01. 727 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 728 ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-shaped, engraved 729 with NPS 550 on one side and scored on both sides. Packaged in bottles of 100 and 500. 730 100’s (bottle): NDC 0004-6203-01; 500’s (bottle): NDC 0004-6203-14. 731 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 732 * ALEVE is a registered trademark of Bayer-Roche L.L.C. 733 734 Distributed by: 735 736 XXXXXXXX 737 Revised: Month/Year 738 Copyright © 1999-2004 by Roche Laboratories Inc. All rights reserved. 739 740 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:38.315739	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17581s99,100,18164s50,51,18965s9,10,20067s4,6lbl.pdf', 'application_number': 20067, 'submission_type': 'SUPPL ', 'submission_number': 4}
12,169	Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- JOEL SCHIFFENBAUER 07/16/2012 Reference ID: 3159401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:38.533823	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018612Orig1s065, 020066Orig1s046lbl.pdf', 'application_number': 20066, 'submission_type': 'SUPPL ', 'submission_number': 46}
12,173	NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 3 EC-NAPROSYN® (naproxen delayed-release tablets) NAPROSYN® (naproxen tablets) ANAPROX®/ANAPROX® DS (naproxen sodium tablets) NAPROSYN® (naproxen suspension) Rx only Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). • Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2- naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen sodium have the following structures, respectively: Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C14H13NaO3. Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 4 NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of naproxen, peach tablets containing 375 mg of naproxen and yellow tablets containing 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone and magnesium stearate. EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-coated white tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The dispersion may also contain simethicone emulsion. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4. ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. The inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Opadry YS-1- 4216. NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle containing sucrose, magnesium aluminum silicate, sorbitol solution and sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to 3.7. CLINICAL PHARMACOLOGY Pharmacodynamics Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Naproxen itself is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 5 Absorption Immediate Release After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. Delayed Release EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC- NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC- NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC: EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61%) AUC0–12 hr (µg·hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 6 concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS, Nursing Mothers). Metabolism Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. In patients with renal failure metabolites may accumulate (see WARNINGS, Renal Effects). Special Populations Pediatric Patients In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN has not been studied in subjects under the age of 18. Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is < 1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Race Pharmacokinetic differences due to race have not been studied. Hepatic Insufficiency Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Renal Insufficiency Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 7 recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS, Renal Effects). CLINICAL STUDIES General Information Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (eg, decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 8 naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC-NAPROSYN and NAPROSYN showed no significant differences in efficacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long-term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. Geriatric Patients The hepatic and renal tolerability of long-term naproxen administration was studied in two double- blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is indicated: • For the relief of the signs and symptoms of rheumatoid arthritis • For the relief of the signs and symptoms of osteoarthritis • For the relief of the signs and symptoms of ankylosing spondylitis • For the relief of the signs and symptoms of juvenile arthritis Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient’s weight. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 9 Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is also indicated: • For relief of the signs and symptoms of tendonitis • For relief of the signs and symptoms of bursitis • For relief of the signs and symptoms of acute gout • For the management of pain • For the management of primary dysmenorrhea EC-NAPROSYN is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated in patients with known hypersensitivity to naproxen and naproxen sodium. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS, Preexisting Asthma). NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDS, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see GI WARNINGS). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 10 Hypertension NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used with caution in patients with fluid retention, hypertension, or heart failure. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen) of sodium, this should be considered in patients whose overall intake of sodium must be severely restricted. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 11 Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see WARNINGS, Advanced Renal Disease). Advanced Renal Disease No information is available from controlled clinical studies regarding the use of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension in patients with advanced renal disease. Therefore, treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is not recommended in these patients with advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 12 PRECAUTIONS General Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. The pharmacological activity of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension should be discontinued. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 13 Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin- sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation). 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 14 observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. 8. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be discontinued. Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE- inhibitors. Aspirin When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is administered with aspirin, its protein binding is reduced, although the clearance of free NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen and naproxen sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as postmarketing observations, have shown that NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 15 Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen with other nonsteroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function. Other Information Concerning Drug Interactions Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of EC-NAPROSYN is not recommended. Drug/Laboratory Test Interaction Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 16 Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found. Pregnancy Teratogenic Effects Pregnancy Category C Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti- inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension on labor and delivery in pregnant women are unknown. Nursing Mothers The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 17 Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. Geriatric Use Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. While age does not appear to be an independent risk factor for the development of peptic ulceration and bleeding with naproxen administration, eElderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS). Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS, Renal Effects). ADVERSE REACTIONS Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 18 Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: edema, palpitations General: dyspnea, thirst *Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal ulceration, ulcerative stomatitis Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction Respiratory: eosinophilic pneumonitis Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 19 In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, hepatitis, eructation, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria OVERDOSAGE Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 20 After observing the response to initial therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient's needs. Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation. Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to the other naproxen formulations (see CLINICAL PHARMACOLOGY). The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS). Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Patients With Moderate to Severe Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects). Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 21 morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY). Juvenile Arthritis The use of NAPROSYN Suspension allows for more flexible dose titration. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see CLINICAL PHARMACOLOGY). The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing of NAPROSYN Suspension: Patient’s Weight Dose Administered as 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). Acute Gout The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). HOW SUPPLIED NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on one side and scored on the other. Packaged in light-resistant bottles of 100. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 22 100’s (bottle): NDC 0004-6313-01. 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6314-01. 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6316-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers. NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28). Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense in light- resistant containers. EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, capsule-shaped, imprinted with EC- NAPROSYN on one side and 375 on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6415-01. 500 mg: white, capsule-shaped, imprinted with EC-NAPROSYN on one side and 500 on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6416-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers. ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with NPS-275 on one side. Packaged in bottles of 100. 100’s (bottle): NDC 0004-6202-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers. ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-shaped, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. 100’s (bottle): NDC 0004-6203-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers. ALEVE is a registered trademark of Bayer Healthcare LLC. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 23 Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non- Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called “corticosteroids” and “anticoagulants” • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 24 Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011 Page 25 Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 This Medication Guide has been approved by the U.S. Food and Drug Administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:39.321865	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017581s106,018164s056,018965s014,020067s011lbl.pdf', 'application_number': 20067, 'submission_type': 'SUPPL ', 'submission_number': 11}
12,168	Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Checkpoint Tag Sensormatic Tag OUTSIDE COPY INSIDE COPY No Copy Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a I II I TO INCREASE YOUR SUCCESS IN QUITTING: 1. You must be motivated to quit. 2. Use Enough - Chew at least 9 pieces of Nicorette per day during the first six weeks. 3. Use Long Enough - Use Nicorette for the full 12 weeks. 4. Use with a support program as directed in the enclosed User’s Guide. To remove Peel off backing, Push the gum, starting at tear off corner with gum 100 PIECES, Q single unit, loose edge. foil. 4mg EACH NOC 01 350467-02 ’A Nicorettei Cinnamon SurgETM Gum Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda THEFT SURVEILLANCE TAG AREA PLACE ANTI-THEFT STICKER HERE Drug Facts (continued) Other information each piece contains: calcium 94mg, sodium 13mg store at 20 - 25°C (68 - 77 ° F) protect from light Inactive ingredients acacia, acesulfame potassium, carnauba wax, D&C yellow #10 Al. lake, edible ink, gum base, hypromellose, magnesium oxide, menthol, natural and artificial cinnamon flavors, peppermint oil, polysorbate 80, sodium carbonate, sucralose, titanium dioxide, xylitol Questions or comments? call toll-free 1-800-419-4766 (English/Spanish) weekdays (9:00 am - 4:30 pm El) Drug Facts Active ingredient (in each chewing piece) Purpose Nicotine polacrilex (equal to 4mg nicotine) Stop smoking aid Use reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Do not use if you continue to smoke, chew tobacco, use snuff, or use a nicotine patch or other nicotine containing products Ask a doctor before use if you have a sodium-restricted diet heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. high blood pressure not controlled with medication. Nicotine can increase blood pressure. stomach ulcer or diabetes Ask a doctor or pharmacist before use if you are using a non-nicotine stop smoking drug taking prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if mouth, teeth or jaw problems occur irregular heartbeat or palpitations occur you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat oral blistering occurs you have symptoms of an allergic reaction (such as difficulty breathing or rash) Keep out of reach of children and pets. Pieces of nicotine gum may have enough nicotine to make children and pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. Directions if you are under 18 years of age, ask a doctor before use before using this product, read the enclosed User’s Guide for complete directions and other important information stop smoking completely when you begin using the gum if you smoke your first cigarette more than 30 minutes after waking up, use 2mg nicotine gum if you smoke your first cigarette within 30 minutes of waking up, use 4mg nicotine gum according to the following 12 week schedule: Weeks 1 t 6 Weeks 7 t 9 Weeks 10 to 12 1 piece every 1 t 2 hours 1 piece every 2 to 4 hours 1 piece every 4 to 8 hours nicotine gum is a medicine and must be used a certain way to get the best results chew the gum slowly until it tingles. Then park it between your cheek and gum. When the tingle is gone, begin chewing again, until the tingle returns. repeat this process until most of the tingle is gone (about 30 minutes) do not eat or drink for 15 minutes before chewing the nicotine gum, or while chewing a piece to improve your chances of quitting, use at least 9 pieces per day for the first 6 weeks if you experience strong or frequent cravings, you may use a second piece within the hour. However, do not continuously use one piece after another since this may cause you hiccups, heartburn, nausea or other side effects. do not use more than 24 pieces a day it is important to complete treatment. Stop using the nicotine gum at the end of 12 weeks. If you still feel the need to use nicotine gum, talk to your doctor. EAS Tagged ' Nicorettet Cinnamon SurgeGum This product is protected in sealed blisters. Do not use if individual blisters or printed backings are broken, open, or torn. Distributed by GlaxoSmithKline Consumer Healthcare, L.P. Moon Township, PA 15108 Made in Sweden @2011 GlaxoSmithKline 00000XX NICOREUE is a registered trademark and the NICORETFE burst design and CINNAMON SURGE are trademarks of the GlaxoSmithKline group of companies. For more information and for a FREE individualized stop smoking program, please visit www.Nicorette.com or see inside for more details. Free Audio CD upon request. See inside. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OPEN HERE TO INCREASE YOUR SUCCESS IN QUITTING: 1. You must be motivated to quit. 2. Use Enough - Chew at least 9 pieces of Nicorette per day during the first six weeks. 3. Use Long Enough - Use Nicorette for the full 12 weeks. 4. Use with a support program as directed in the enclosed User’s Guide. To remove Peel off backing, Push the gum, starting at gum tear off corner with _ _ through single unit, loose edge. 110 PIECES, 4mg EACH NDC 0135-0158-07 NicorettØ nicotine polacrilex gum, 4mg stop smoking aid Original 110 PIECES, 4mg EACH Nicorettei Original Gum Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda THEFT SURVEILLANCE TAG AREA PLACE ANTI-THEFT STICKER HERE Drug Facts (continued) Other information each piece contains; calcium 117mg, sodium 13mg store at 20 - 25°C (68 - 77°F) protect from light Inactive ingredients D&C yellow #10, flavors, glycerin, gum base, sodium carbonate, sorbitol Questions or comments? call toll-free 1-800-419-4766 (English/Spanish) weekdays (9:00 am - 4:30 pm El) Drug Facts Active ingredient (in each chewing piece) Purpose Nicotine polacrilex (equal to 4mg nicotine) Stop smoking aid Use reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Do not use if you continue to smoke, chew tobacco, use snuff, or use a nicotine patch or other nicotine containing products Ask a doctor before use if you have a sodium-restricted diet heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. high blood pressure not controlled with medication. Nicotine can increase blood pressure. stomach ulcer or diabetes Ask a doctor or pharmacist before use if you are using a non-nicotine stop smoking drug taking prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if mouth, teeth or jaw problems occur irregular heartbeat or palpitations occur you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat you have symptoms of an allergic reaction (such as difficulty breathing or rash) Keep out of reach of children and pets. Pieces of nicotine gum may have enough nicotine to make children and pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. Directions if you are under 18 years of age, ask a doctor before use before using this product, read the enclosed User’s Guide for complete directions and other important information stop smoking completely when you begin using the gum if you smoke your first cigarette more than 30 minutes after waking up, use 2mg nicotine gum if you smoke your first cigarette within 30 minutes of waking up, use 4mg nicotine gum according to the following 12 week schedule: Weeks 1 t 6 Weeks 7to 9 Weeks 101012 1 piece every 1 t 2 hours 1 piece every 2 to 4 hours 1 piece every 4 to 8 hours nicotine gum is a medicine and must be used a certain way to get the best results chew the gum slowly until it tingles. Then park it between your cheek and gum. When the tingle is gone, begin chewing again, until the tingle returns. repeat this process until most of the tingle is gone (about 30 minutes) do not eat or drink for 15 minutes before chewing the nicotine gum, or while chewing a piece to improve your chances of quitting, use at least 9 pieces per day for the first 6 weeks if you experience strong or frequent cravings, you may use a second piece within the hour. However, do not continuously use one piece after another since this may cause you hiccups, heartburn, nausea or other side effects. do not use more than 24 pieces a day it is important to complete treatment. Stop using the nicotine gum at the end of 12 weeks. If you still feel the need to use nicotine gum, talk to your doctor. 119 1 EAS Tagged 0766-7847-08 NicorettO Original Gum This product is protected in sealed blisters. Do not use if individual blisters or printed backings are broken, open, or torn. Distributed by Glaxosmithkline Consumer Healthcare, L.P. Moon Township, PA 15108 Made in Sweden @2011 GlaxoSmithKline 00000XX NICORETIE is a registered trademark and the NICORETTE burst design is a trademark of the GlaxoSmithKiine group of companies. For more information and for a FREE individualized stop smoking prograin, please visit wwwNicorelfe.con; or see inside for more details. Free Audio CD upon request. See inside. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda !G urn 20 PIECES, 4mg EACH 0 Pocket Pack of 20) OUTSIDE COPY C__~2~ Drug Facts Active ingredient (in each chewing piece) Purpose Nicotine polacrilex (equal to 4mg nicotine).......................Stop smoking aid Use reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Do not use if you continue to smoke, chew tobacco, use snuff, or use a nicotine patch or other nicotine containing products Ask a doctor before use if you have a sodium-restricted diet heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. high blood pressure not controlled with medication. Nicotine can increase blood pressure. stomach ulcer or diabetes Ask a doctor or pharmacist before use if you are using a non-nicotine stop smoking drug taking prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if mouth, teeth or jaw problems occur irregular heartbeat or palpitations occur you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat oral blistering occurs you have symptoms of an allergic reaction (such as difficulty breathing or rash) w Flip open for Directions and additional information Retain this package for complete product information The gum is contained in a carton packaged inside a clear plastic outer container sealed to a printed card. The inner carton has a clear overwrap. DO NOT USE IF ANY OF THESE TAMPER EVIDENT FEATURES ARE MISSING, TORN, OR BROKEN. I - 3 U .159-74 4 Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INSIDE COPY C:2= To INCREASE YOUR SUCCESS IN QUITTING: 1. You must be motivated to quit. 2. Use Enough - Chew at least 9 pieces of Nicorette per day during the first six weeks. 3. Use Long Enough - Use Nicorette for the full 12 weeks. 4. Use with a support program as directed in the enclosed User’s Guide. How To Open the Nicorette Gum Pocket Pack Dispense Nicorette Gum and follow dosing .. instructions. .. . For more information and for a FREE individualized stop smoking program, please visit www.Nicorette.com or see inside for more details. Free Audio CD upon request. See inside. Distributed by GlaxoSmtthKline Consumer Healthcare, L.P. Moon Township, PA 15108, Made in Sweden 02011 GlaxoSmithKline NICORETTE is a registered trademark and the MCORETTE burst design and CINNAMON SURGE are trademarks of the GlaxoSmithKline group of companies. 00000XX Drug Facts (continued) I Keep out of reach of children and pets. Pieces of nicotine gum may have enough nicotine to make children and pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. Directions if you are under 18 years of age, ask a doctor before use before using this product, read the enclosed User’s Guide for complete directions and other important information stop smoking completely when you begin using the gum if you smoke your first cigarette more than 30 minutes after waking up, use 2mg nicotine gum if you smoke your first cigarette within 30 minutes of waking up, use 4mg nicotine gum according to the following 12 week schedule: Weeks 1 t 6 Weeks 7 to 9 Weeks 10 to 12 1 piece every 1 to2hours 1 piece every 1 2to4 hours 1 piece every 1 4to8 hours nicotine gum is a medicine and must be used a certain way to get the best results chew the gum slowly until it tingles. Then park it between your cheek and gum. When the tingle is gone, begin chewing again, until the tingle returns. repeat this process until most of the tingle is gone (about 30 minutes) do not eat or drink for 15 minutes before chewing the nicotine gum, or while chewing a piece to improve your chances of quitting, use at least 9 pieces per day for the first 6 weeks if you experience strong or frequent cravings, you may use a second piece within the hour. However, do not continuously use one piece after another since this may cause you hiccups, heartburn, nausea or other side effects. do not use more than 24 pieces a day it is important to complete treatment. Stop using the nicotine gum at the end of 12 weeks. If you still feel the need to use nicotine gum, talk to your doctor. Other information each piece contains: calcium 94mg, sodium 13mg store at 20 - 25°C (68 - 77°F) protect from light and humidity Inactive ingredients acacia, acesulfame potassium, carnauba wax, D&C yellow #10 Al. lake, edible ink, gum base, hypromellose, magnesium oxide, menthol, natural and artificial cinnamon flavors, peppermint oil, polysorbate 80, sodium carbonate, sucralose, titanium dioxide, xylitol Questions or comments? call toll-free 1-800-419-4766 (English/Spanish) weekdays (9:00 am - 4:30 pm ET) Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Facts Active ingredient (in each chewing piece) Purpose Nicotine polacrilex (equal to 4mg nicotine).......................Stop smoking aid Use • reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Do not use • if you continue to smoke, chew tobacco, use snuff, or use a nicotine patch or other nicotine containing products Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. • high blood pressure not controlled with medication. Nicotine can increase blood pressure. • stomach ulcer or diabetes Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if • mouth, teeth or jaw problems occur • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat • you have symptoms of an allergic reaction (such as difficulty breathing or rash) ■ not for sale to those under 18 years of age ■ proof of age required ■ not for sale in vending machines or from any source where proof of age cannot be verified Flip open for Directions and additional information Retain this package for complete product information The gum is contained in a carton packaged inside a clear plastic outer container sealed to a printed card. The inner carton has a clear overwrap. DO NOT USE IF ANY OF THESE TAMPER EVIDENT FEATURES ARE MISSING, TORN, OR BROKEN. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. HOW TO USE NICOrette GUM TO HELP YOU QUIT SMOKING. nicotine polacrilex gum 2mg and 4mg User’s Guide 2mg and 4mg User’s Guide ® ® ® (101837XA) NRO Gum UG Booklet.indd 1 (101837XA) NRO Gum UG Booklet.indd 1 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. (See insert) ENROLL NOW! ® ® (101837XA) NRO Gum UG Booklet.indd 2 (101837XA) NRO Gum UG Booklet.indd 2 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. keys to success. 1) You must really want to quit smoking for Nicorette® Gum to help you. 2) You can greatly increase your chances for success by using at least 9 to 12 pieces every day when you start using Nicorette Gum. See page 12. 3) You should continue to use Nicorette Gum as explained in this User’s Guide for 12 full weeks. 4) Nicorette Gum works best when used together with a support program — See page 3 for details. 5) If you have trouble using Nicorette Gum, ask your doctor or pharmacist or call GlaxoSmithKline at 1-800-419-4766 weekdays (10:00 am - 4:30 pm ET). 6) To request a free audio CD containing tips to help make quitting easier, call the toll free number listed above. (ONE CD PER CUSTOMER) 1 (101837XA) NRO Gum UG Booklet.indd 3 (101837XA) NRO Gum UG Booklet.indd 3 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 2 SO YOU DECIDED TO QUIT. If you’ve tried to quit before and haven’t succeeded, don’t be discouraged! Quitting isn’t easy. It takes time, and most people try a few times before they are successful. The important thing is to try again until you succeed. This User’s Guide will give you support as you become a non-smoker. It will answer common questions about Nicorette Gum and give tips to help you stop smoking, and should be referred to often. Congratulations. Your decision to stop smoking is an important one. That’s why you’ve made the right choice in choosing Nicorette Gum. Your own chances of quitting smoking depend on how much you want to quit, how strongly you are addicted to tobacco, and how closely you follow a quitting program like the one that comes with Nicorette Gum. QuittinG Smoking is hard! (101837XA) NRO Gum UG Booklet.indd 4 (101837XA) NRO Gum UG Booklet.indd 4 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 3 If you ﬁ nd you cannot stop smoking or if you start smoking again after using Nicorette Gum, remember breaking this addiction doesn’t happen overnight. You may want to talk to a health care professional who can help you improve your chances of quitting the next time you try Nicorette Gum or another method. Your reason for quitting may be a combination of concerns about health, the effect of smoking on your appearance, and pressure from your family You are more likely to stop smoking by using Nicorette Gum with a support program that helps you break your smoking habit. There may be support groups in your area for people trying to quit. Call your local chapter of the American Lung Association, American Cancer Society or American Heart Association for further information. Toll free phone numbers are printed on the Wallet Card on the back cover of this User’s Guide. LET’S GET ORGaNIZED. where to get help. (101837XA) NRO Gum UG Booklet.indd 5 (101837XA) NRO Gum UG Booklet.indd 5 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. Smoking is addictive in two ways. Your need for nicotine has become both physical and mental. You must overcome both addictions to stop smoking. So while Nicorette Gum will lessen your body’s physical addiction to nicotine, you’ve got to want to quit smok- ing to overcome the mental dependence on cigarettes. Once you’ve decided that you’re going to quit, it’s time to get started. But ﬁ rst, there are some important warn- ings you should consider. and friends to stop smoking. Or maybe you’re concerned about the dangerous effect of second-hand smoke on the people you care about. All of these are good reasons. You probably have others. Decide your most important reasons, and write them down on the wallet card inside the back cover of this User’s Guide. Carry this card with you. In difﬁ cult moments, when you want to smoke, the card will remind you why you are quitting. WHAT YOU’RE UP AGAINST. 4 (101837XA) NRO Gum UG Booklet.indd 6 (101837XA) NRO Gum UG Booklet.indd 6 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. This product is only for those who want to stop smoking. If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Some important WARNINGS. Do not use • if you continue to smoke, chew tobacco, use snuff, or use a nicotine patch or other nicotine containing products. Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. • high blood pressure not controlled with medication. Nicotine can increase your blood pressure. • stomach ulcer or diabetes 5 (101837XA) NRO Gum UG Booklet.indd 7 (101837XA) NRO Gum UG Booklet.indd 7 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 6 Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking a prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if • mouth, teeth or jaw problems occur • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat • oral blistering occurs • you have symptoms of an allergic reaction (such as difﬁ culty breathing or rash) Keep out of reach of children and pets. Pieces of nicotine gum may have enough nicotine to make children and pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. Becoming a non-smoker starts today. First, check that you bought the right starting dose. If you smoke your ﬁ rst cigarette within 30 minutes of waking up, use 4mg nicotine gum. If you smoke your ﬁ rst cigarette more than 30 minutes after waking up, use 2mg LET’S GET STARTED. (101837XA) NRO Gum UG Booklet.indd 8 (101837XA) NRO Gum UG Booklet.indd 8 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 7 nicotine gum. Next, read through the en- tire User’s Guide carefully. Then, set your personalized quitting schedule. Take out a calendar that you can use to track your progress, and identify four dates, using the stickers in the center of this User’s Guide: STEP 1. (Weeks 1-6). Your quit date (and the day you’ll start using Nicorette Gum). Choose your quit date (it should be soon). This is the day you will quit smoking ciga- rettes entirely and begin using Nicorette Gum to satisfy your cravings for nicotine. For the ﬁ rst six weeks, you’ll use a piece of Nicorette Gum every hour or two. Be sure to follow the directions starting on pages 10 and 12. Place the Step 1 stickers on this date. STEP 2. (Weeks 7 to 9). The day you’ll start reducing your use of Nicorette Gum. After six weeks, you’ll begin gradually reducing your Nicorette Gum usage to one piece every two to four hours. Place the Step 2 sticker on this date (the ﬁ rst day of week seven). STEP 3. (Weeks 10-12). The day you’ll further reduce your use of Nicorette Gum. (101837XA) NRO Gum UG Booklet.indd 9 (101837XA) NRO Gum UG Booklet.indd 9 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 8 Nine weeks after you begin using Nicorette Gum, you will further reduce your nicotine intake by using one piece every four to eight hours. Place the Step 3 sticker on this date (the ﬁ rst day of week ten). For the next three weeks, you’ll use a piece of Nicorette Gum every four to eight hours. End of treatment: The day you’ll complete Nicorette Gum therapy. Nicorette Gum should not be used for longer than twelve weeks. Identify the date thirteen weeks after the date you chose in Step 1, and place the “EX-SMOKER” sticker on your calendar. Because smoking is an addiction, it is not easy to stop. After you’ve given up cigarettes, you will still have a strong urge to smoke. Plan ahead NOW for these times, so you’re not defeated in a moment of weakness. The following tips may help: • Keep the phone numbers of supportive friends and family members handy. • Keep a record of your quitting process. Track the number of Nicorette Gum pieces you use each day, and whether you feel a craving for cigarettes. In the event that PLAN AHEAD. (101837XA) NRO Gum UG Booklet.indd 10 (101837XA) NRO Gum UG Booklet.indd 10 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 9 you slip, immediately stop smoking and resume your quit attempt with the Nicorette Gum program. • Put together an Emergency Kit that includes items that will help take your mind off occasional urges to smoke. Include cinnamon gum or lemon drops to suck on, a relaxing CD, and something for your hands to play with, like a smooth rock, rubber band, or small metal balls. • Set aside some small rewards, like a new magazine or a gift certiﬁ cate from your favorite store, which you’ll “give” yourself after passing difﬁ cult hurdles. • Think now about the times when you most often want a cigarette, and then plan what else you might do instead of smoking. For instance, you might plan to take your coffee break in a new location, or take a walk right after dinner, so you won’t be tempted to smoke. (101837XA) NRO Gum UG Booklet.indd 11 (101837XA) NRO Gum UG Booklet.indd 11 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. the addictive part of cigarette smoke. Nicotine can cause side effects such as headache, nausea, upset stomach, and dizziness. If you are under 18 years of age, ask a doctor before use. Before you can use Nicorette Gum correctly, you have to prac- tice! That sounds silly, but it isn’t. Nicorette Gum isn’t like ordinary chewing gum. It’s a medicine, and must be chewed a certain way to work right. Chewed like ordinary gum, Nicorette Gum won’t work well and Nicorette Gum’s sug- ar-free chewing pieces provide nicotine to your system – they work as a temporary aid to help you quit smoking by reducing nicotine withdrawal symptoms. Nicorette Gum provides a lower level of nicotine to your blood than ciga- rettes, and allows you to gradually do away with your body’s need for nicotine. Because Nicorette Gum does not contain the tar or carbon monoxide of cigarette smoke, it does not have the same health dangers as tobacco. However, it still delivers nicotine, 10 HOW NICOrette gum works. HOW To Use NICOrette gum. (101837XA) NRO Gum UG Booklet.indd 12 (101837XA) NRO Gum UG Booklet.indd 12 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. can cause side effects. An overdose can occur if you chew more than one piece of Nicorette Gum at the same time, or if you chew many pieces one after another. Read all the following instructions before using Nicorette Gum. Refer to them often to make sure you’re using Nicorette Gum correctly. If you chew too fast, or do not chew correctly, you may get hiccups, heart- burn, or other stomach problems. Don’t eat or drink for 15 minutes before using Nicorette Gum, or while chewing a piece. The effectiveness of Nicorette Gum may be reduced by some foods and drinks, such as 11 coffee, juices, wine or soft drinks. 1) Stop smoking completely before you start using Nicorette Gum. 2) To reduce craving and other withdrawal symptoms, use Nicorette Gum according to the dosage schedule on page 12. 3) Chew each Nicorette Gum piece very slowly several times. 4) Stop chewing when you notice a peppery taste, or a slight tingling in your mouth. (This usually happens after about 15 chews, but may vary from person to person.) (101837XA) NRO Gum UG Booklet.indd 13 (101837XA) NRO Gum UG Booklet.indd 13 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 12 5) “PARK” the Nicorette Gum piece between your cheek and gum, and leave it there. 6) When the peppery taste or tingle is almost gone (in about a minute), start to chew a few times slowly again. When the taste or tingle returns, stop again. 7) Park the Nicorette Gum piece again (in a different place in your mouth). 8) Repeat steps 3 to 7 (chew, chew, park) until most of the nicotine is gone from the Nicorette Gum piece (usually happens in about half an hour; the peppery taste or tingle won’t return.) 9) Wrap the used Nicorette Gum piece in paper and throw away in the trash. To improve your chances of quitting, use at least 9 pieces of Nicorette Gum a day. If you experience strong or frequent cravings, you may use a second piece within the hour. However, do not continuously use one The following chart lists the recommended usage schedule for Nicorette Gum: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 piece every 1 piece every 1 piece every 1 to 2 hours 2 to 4 hours 4 to 8 hours DO NOT USE MORE THAN 24 PIECES PER DAY. (101837XA) NRO Gum UG Booklet.indd 14 (101837XA) NRO Gum UG Booklet.indd 14 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ENROLL NOW! A Personal Invitation to Join brought to you by ® ® ® (101837XA) NRO Gum UG Booklet.indd 15 (101837XA) NRO Gum UG Booklet.indd 15 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda is a FREE custom-tailored plan to help you break your psychological addiction to smoking — while NICORETTE Gum ﬁ ghts the physical addiction. To get your plan, call toll free 1-800-770-0708 or visit us on the Web at www.committedquitters.com. Having a Plan Will Help You Quit To Enroll Call Now 1-800-770-0708 or enroll online at www.committedquitters.com ® ® ® (101837XA) NRO Gum UG Booklet.indd 16 (101837XA) NRO Gum UG Booklet.indd 16 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHEN YOU CALL: You will be asked a few questions to understand YOU and YOUR speciﬁ c needs. AFTER YOU CALL: In a few days, you will receive your custom-tailored stop smoking plan. You will continue to receive personal, custom-tailored support — six times during the next twelve weeks. (101837XA) NRO Gum UG Booklet.indd 17 (101837XA) NRO Gum UG Booklet.indd 17 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Your Plan Will Contain: 12-week stop smoking plan Newsletter with stories from other successful quitters Motivational postcard Week 1 Week 2 Week 3 (101837XA) NRO Gum UG Booklet.indd 18 (101837XA) NRO Gum UG Booklet.indd 18 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Materials are subject to change. More tips on quitting Congratulations Packet Award Certiﬁ cate Week 6 Week 9 Week 12 (101837XA) NRO Gum UG Booklet.indd 19 (101837XA) NRO Gum UG Booklet.indd 19 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How To Survive the First Week: Quitting Tips 3. Stay active. Keep busy to take your mind off smoking. 4. Think positive! The ﬁ rst week is the toughest. Remind yourself that it will get easier. Use the sample of the Stop Smoking Plan (see next page) to get you through the ﬁ rst week until your materials arrive. 1. Control your physical cravings for nicotine. Use enough – You can greatly increase your chances for success by using at least 9 to 12 pieces every day when you start using Nicorette Gum. 2. Get rid of all signs that you ever smoked — ashtrays, matches and, of course, cigarettes. (101837XA) NRO Gum UG Booklet.indd 20 (101837XA) NRO Gum UG Booklet.indd 20 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Day Pieces Chewed Planning: Plan ahead. Note events here that will tempt you to smoke, and how you will deal with them. 1. _________ _______________________________________________________________ 2. _________ _______________________________________________________________ 3. _________ _______________________________________________________________ 4. _________ _______________________________________________________________ 5. _________ _______________________________________________________________ 6. _________ _______________________________________________________________ 7. _________ _______________________________________________________________ The toughest hurdle — your ﬁ rst week without cigarettes. Your craving for nicotine will be strongest during this ﬁ rst week. To deal with physical withdrawal, use Nicorette Gum properly. Follow the directions on your Nicorette Gum package. WEEK ONE CALENDAR ✁ If you have gone back to smoking, call 1-800-770-0708 to order relapse information. • Make sure you tell friends and family members that you quit. • Use enough Nicorette Gum — at least 9 to 12 pieces per day. • Stay active. Keep busy to take your mind off smoking. • When an urge to smoke strikes, take a few deep breaths and remind yourself how important quitting is to you. TIPS Carry this calendar with you. (101837XA) NRO Gum UG Booklet.indd 21 (101837XA) NRO Gum UG Booklet.indd 21 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ©2011 GlaxoSmithKline The Committed Quitters ® program is a plan speciﬁ cally individualized for you. Call Between 7 am and 12 Midnight ET or enroll online 24 hours a day. (ONE PLAN PER CUSTOMER) NICORETTE and COMMITTED QUITTERS are registered trademarks, and associated logo designs and overall dress designs are trademarks owned and/or licensed to the GlaxoSmithKline group of companies. Read and follow label directions (101837XA) NRO Gum UG Booklet.indd 22 (101837XA) NRO Gum UG Booklet.indd 22 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 13 piece after another, since this may cause you hiccups, heartburn, nausea or other side effects. The goal of using Nicorette Gum is to slowly reduce your dependence on nico- tine. The schedule for using Nicorette Gum will help you reduce your nicotine craving gradually as you reduce and then stop your use of Nicorette Gum. Here are some tips to help you cut back during each step and then stop using Nicorette Gum: HOW to reduce your nicorette GUM usage. • After a while, start chewing each Nicorette Gum piece for only 10 to 15 minutes, instead of half an hour. Then, gradually begin to reduce the number of pieces used. • Or, try chewing each piece for longer than half an hour, but reduce the number of pieces you use each day. • Substitute ordinary chewing gum for some of the Nicorette Gum pieces you would normally use. Increase the number of pieces of ordinary gum as you cut back on the Nicorette Gum pieces. (101837XA) NRO Gum UG Booklet.indd 23 (101837XA) NRO Gum UG Booklet.indd 23 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 14 • Check how well you’ve reduced your daily usage of Nicorette Gum in Weeks 10 to 12. You should only be using about 3 to 5 pieces a day. Get ready to stop. STOP USING NICORETTE GUM AT THE END OF WEEK 12. The following tips may help you with stopping Nicorette Gum at the end of 12 weeks. • Set a stop date. • Use the same number of pieces of confectionery gum or mints as you were using Nicorette Gum per day. At the times when you have an urge to use Nicorette Gum, use a strong ﬂ avored gum or mint such as cinnamon or peppermint. • Reduce the number of pieces of gum or mints you use by one piece per day until you do not need to use any gum or mints. Talk to your doctor if you: • still feel the need to use Nicorette Gum at the end of week 12 • start using Nicorette Gum again after stopping • start smoking again (101837XA) NRO Gum UG Booklet.indd 24 (101837XA) NRO Gum UG Booklet.indd 24 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 15 Within the ﬁ rst few weeks of giving up smoking, you may be tempted to smoke for pleasure, particularly after completing a difﬁ cult task, or at a party or bar. Here are some tips to help get you through the important ﬁ rst stages of becoming a non-smoker: On Your Quit Date: • Ask your family, friends and co-workers to support you in your efforts to stop smoking. TIPS TO MAKE QUITTING EASIER. • Throw away all your cigarettes, matches, lighters, ashtrays, etc. • Keep busy on your quit day. Exercise. Go to a movie. Take a walk. Get together with friends. • Figure out how much money you’ll save by not smoking. Most ex-smokers can save more than $1,000 a year. • Write down what you will do with the money you save. (101837XA) NRO Gum UG Booklet.indd 25 (101837XA) NRO Gum UG Booklet.indd 25 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 16 • Know your high risk situations and plan ahead how you will deal with them. • Keep Nicorette Gum near your bed, so you’ll be prepared for any nicotine cravings when you wake up in the morning. • Visit your dentist and have your teeth cleaned to get rid of the tobacco stains. Right after Quitting: • During the ﬁ rst few days after you’ve stopped smoking, spend as much time as possible at places where smoking is not allowed. • Drink large quantities of water and fruit juices. • Try to avoid alcohol, coffee and other beverages you associate with smoking. • Remember that temporary urges to smoke will pass, even if you don’t smoke a cigarette. • Keep your hands busy with something like a pencil or a paper clip. • Find other activities which help you relax without cigarettes. • Swim, jog, take a walk, play basketball. (101837XA) NRO Gum UG Booklet.indd 26 (101837XA) NRO Gum UG Booklet.indd 26 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 17 stop smoking, you might feel edgy and nervous and have trouble concentrating. You might get headaches, feel dizzy and a little out of sorts, feel sweaty or have stomach upsets. You might even have trouble sleeping at ﬁ rst. These are typical withdrawal symptoms that will go away with time. Your smoker’s cough will get worse before it gets better. But don’t worry, that’s a good sign. Coughing helps clear the tar deposits out of your lungs. what to expect. • Don’t worry too much about gaining weight. Watch what you eat, take time for daily exercise, and change your eating habits if you need to. • Laughter helps. Watch or read something funny. Your body is now coming back into balance. During the ﬁ rst few days after you (101837XA) NRO Gum UG Booklet.indd 27 (101837XA) NRO Gum UG Booklet.indd 27 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 18 After A Week Or Two. By now you should be feeling more conﬁ dent that you can handle those smoking urges. Many of your withdrawal symptoms have left by now, and you should be noticing some positive signs: less coughing, better breathing and an improved sense of taste and smell, to name a few. After A Month. You probably have the urge to smoke much less often now. But urges may still occur, and when they do, they are likely to be powerful ones that come out of nowhere. Don’t let them catch you off guard. Plan ahead for these difﬁ cult times. Concentrate on the ways non-smokers are more attractive than smokers. Their skin is less likely to wrinkle. Their teeth are whiter, cleaner. Their breath is fresher. Their hair and clothes smell better. That cough that seems to make even a laugh sound more like a rattle is a thing of the past. Their children and others around them are healthier, too. (101837XA) NRO Gum UG Booklet.indd 28 (101837XA) NRO Gum UG Booklet.indd 28 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 19 What To Do About Relapse. What should you do if you slip and start smoking again? The answer is simple. A lapse of one or two or even a few cigarettes has not spoiled your efforts! Discard your cigarettes, forgive yourself and try again. If you start smoking again, keep your box of Nicorette Gum for your next quit attempt. If you have taken up regular smoking again, don’t be discouraged. Research shows that the best thing you can do is to try again. The important thing is to learn from your last attempt. • Admit that you’ve slipped, but don’t treat yourself as a failure. • Try to identify the “trigger” that caused you to slip, and prepare a better plan for dealing with this problem next time. • Talk positively to yourself – tell yourself that you have learned something from this experience. • Make sure you used Nicorette Gum correctly over the full 12 weeks to reduce your craving for nicotine. • Remember that it takes practice to do (101837XA) NRO Gum UG Booklet.indd 29 (101837XA) NRO Gum UG Booklet.indd 29 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 20 anything, and quitting smoking is no exception. Once you’ve stopped smoking, take a second and pat yourself on your back. Now do it again. You deserve it. Remember now why you decided to stop smoking in the ﬁ rst place. Look at your list of reasons. Read them again. And smile. Now think about all the money you are saving and what you’ll do with it. All the non-smoking places you can go, and what you might do there. WHEN THE struggle IS over. All those years you may have added to your life, and what you’ll do with them. Remember that temptation may not be gone forever. However, the hard part is behind you so look forward with a positive attitude, and enjoy your new life as a non-smoker. QUESTIONS & ANSWERS. 1. How will I feel when I stop smoking and start using Nicorette Gum? You’ll need to prepare yourself for some nicotine withdrawal symptoms. These begin almost immediately after you stop (101837XA) NRO Gum UG Booklet.indd 30 (101837XA) NRO Gum UG Booklet.indd 30 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 21 smoking, and are usually at their worst during the ﬁ rst three or four days. Understand that any of the following is possible: • craving for cigarettes • anxiety, irritability, restlessness, mood changes, nervousness • drowsiness • trouble concentrating • increased appetite and weight gain • headaches, muscular pain, constipation, fatigue. Nicorette Gum can help provide relief from withdrawal symptoms such as irritability and nervousness, as well as the craving for nicotine you used to satisfy by having a cigarette. 2. Is Nicorette Gum just substituting one form of nicotine for another? Nicorette Gum does contain nicotine. The purpose of Nicorette Gum is to provide you with enough nicotine to help control the physical withdrawal symptoms so you can deal with the mental aspects of quitting. Dur- ing the 12 week program, you will gradually (101837XA) NRO Gum UG Booklet.indd 31 (101837XA) NRO Gum UG Booklet.indd 31 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 22 reduce your nicotine intake by switching to fewer pieces each day. Remember, don’t use Nicorette Gum together with nicotine patches or other nicotine containing products. 3. Can I be hurt by using Nicorette Gum? For most adults, the amount of nicotine in the gum is less than from smoking. Some people will be sensitive to even this amount of nicotine and should not use this product without advice from their doctor (see page 5). Because Nicorette Gum is a gum-based product, chewing it can cause dental ﬁ llings to loosen and aggravate other mouth, tooth and jaw problems. Nicorette Gum can also cause hiccups, heartburn and other stomach problems especially if chewed too quickly or not chewed correctly. 4. Will I gain weight? Many people do tend to gain a few pounds the ﬁ rst 8-10 weeks after they stop smok- ing. This is a very small price to pay for the enormous gains that you will make in your overall health and attractiveness. If you (101837XA) NRO Gum UG Booklet.indd 32 (101837XA) NRO Gum UG Booklet.indd 32 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 23 continue to gain weight after the ﬁ rst two months, try to analyze what you’re doing differently. Reduce your fat intake, choose healthy snacks, and increase your physical activity to burn off the extra calories. 5. Is Nicorette Gum more expensive than smoking? The total cost of Nicorette Gum for the twelve week program is about equal to what a person who smokes one and a half packs of cigarettes a day would spend on cigarettes for the same period of time. Also, use of Nicorette Gum is only a short-term cost, while the cost of smoking is a long-term cost, because of the health problems smoking causes. 6. What if I slip up? Discard your cigarettes, forgive yourself and then get back on track. Don’t consider yourself a failure or punish yourself. In fact, people who have already tried to quit are more likely to be successful the next time. (101837XA) NRO Gum UG Booklet.indd 33 (101837XA) NRO Gum UG Booklet.indd 33 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda GOOD LUCK! Recommended dosage schedule for Nicorette Gum: STEP 1 STEP 2 STEP 3 weeks 1 to 6 1 piece every 1 to 2 hours weeks 7 to 9 1 piece every 2 to 4 hours weeks 10 to 12 1 piece every 4 to 8 hours 00000XX Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. (101837XA) NRO Gum UG Booklet.indd 34 (101837XA) NRO Gum UG Booklet.indd 34 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. My most important reasons to quit smoking are: WALLET CARD (101837XA) NRO Gum UG Booklet.indd 35 (101837XA) NRO Gum UG Booklet.indd 35 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. WHERE TO CALL FOR HELP WALLET CARD American Lung Association 1-800-586-4872 American Cancer Society 1-800-227-2345 American Heart Association 1-800-242-8721 (101837XA) NRO Gum UG Booklet.indd 36 (101837XA) NRO Gum UG Booklet.indd 36 1/12/12 2:21 PM 1/12/12 2:21 PM Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. HOW TO USE NICOrette GUM TO HELP YOU QUIT SMOKING. nicotine polacrilex gum 2mg and 4mg User’s Guide 2mg and 4mg User’s Guide ® ® ® Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. (See insert) ENROLL NOW! ® ® Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. keys to success. 1) You must really want to quit smoking for Nicorette® Gum to help you. 2) You can greatly increase your chances for success by using at least 9 to 12 pieces every day when you start using Nicorette Gum. See page 12. 3) You should continue to use Nicorette Gum as explained in this User’s Guide for 12 full weeks. 4) Nicorette Gum works best when used together with a support program — See page 3 for details. 5) If you have trouble using Nicorette Gum, ask your doctor or pharmacist or call GlaxoSmithKline at 1-800-419-4766 weekdays (10:00 am - 4:30 pm ET). 6) To request a free audio CD containing tips to help make quitting easier, call the toll free number listed above. (ONE CD PER CUSTOMER) 1 Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 2 SO YOU DECIDED TO QUIT. If you’ve tried to quit before and haven’t succeeded, don’t be discouraged! Quitting isn’t easy. It takes time, and most people try a few times before they are successful. The important thing is to try again until you succeed. This User’s Guide will give you support as you become a non-smoker. It will answer common questions about Nicorette Gum and give tips to help you stop smoking, and should be referred to often. Congratulations. Your decision to stop smoking is an important one. That’s why you’ve made the right choice in choosing Nicorette Gum. Your own chances of quitting smoking depend on how much you want to quit, how strongly you are addicted to tobacco, and how closely you follow a quitting program like the one that comes with Nicorette Gum. QuittinG Smoking is hard! Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 3 If you ﬁ nd you cannot stop smoking or if you start smoking again after using Nicorette Gum, remember breaking this addiction doesn’t happen overnight. You may want to talk to a health care professional who can help you improve your chances of quitting the next time you try Nicorette Gum or another method. Your reason for quitting may be a combination of concerns about health, the effect of smoking on your appearance, and pressure from your family You are more likely to stop smoking by using Nicorette Gum with a support program that helps you break your smoking habit. There may be support groups in your area for people trying to quit. Call your local chapter of the American Lung Association, American Cancer Society or American Heart Association for further information. Toll free phone numbers are printed on the Wallet Card on the back cover of this User’s Guide. LET’S GET ORGaNIZED. where to get help. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. Smoking is addictive in two ways. Your need for nicotine has become both physical and mental. You must overcome both addictions to stop smoking. So while Nicorette Gum will lessen your body’s physical addiction to nicotine, you’ve got to want to quit smok- ing to overcome the mental dependence on cigarettes. Once you’ve decided that you’re going to quit, it’s time to get started. But ﬁ rst, there are some important warn- ings you should consider. and friends to stop smoking. Or maybe you’re concerned about the dangerous effect of second-hand smoke on the people you care about. All of these are good reasons. You probably have others. Decide your most important reasons, and write them down on the wallet card inside the back cover of this User’s Guide. Carry this card with you. In difﬁ cult moments, when you want to smoke, the card will remind you why you are quitting. WHAT YOU’RE UP AGAINST. 4 Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. This product is only for those who want to stop smoking. If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Some important WARNINGS. Do not use • if you continue to smoke, chew tobacco, use snuff, or use a nicotine patch or other nicotine containing products. Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. • high blood pressure not controlled with medication. Nicotine can increase your blood pressure. • stomach ulcer or diabetes 5 Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 6 Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking a prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if • mouth, teeth or jaw problems occur • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat • you have symptoms of an allergic reaction (such as difﬁ culty breathing or rash) Keep out of reach of children and pets. Pieces of nicotine gum may have enough nicotine to make children and pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. Becoming a non-smoker starts today. First, check that you bought the right starting dose. If you smoke your ﬁ rst cigarette within 30 minutes of waking up, use 4mg nicotine gum. If you smoke your ﬁ rst cigarette more than 30 minutes after waking up, use 2mg LET’S GET STARTED. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 7 nicotine gum. Next, read through the en- tire User’s Guide carefully. Then, set your personalized quitting schedule. Take out a calendar that you can use to track your progress, and identify four dates, using the stickers in the center of this User’s Guide: STEP 1. (Weeks 1-6). Your quit date (and the day you’ll start using Nicorette Gum). Choose your quit date (it should be soon). This is the day you will quit smoking ciga- rettes entirely and begin using Nicorette Gum to satisfy your cravings for nicotine. For the ﬁ rst six weeks, you’ll use a piece of Nicorette Gum every hour or two. Be sure to follow the directions starting on pages 10 and 12. Place the Step 1 stickers on this date. STEP 2. (Weeks 7 to 9). The day you’ll start reducing your use of Nicorette Gum. After six weeks, you’ll begin gradually reducing your Nicorette Gum usage to one piece every two to four hours. Place the Step 2 sticker on this date (the ﬁ rst day of week seven). STEP 3. (Weeks 10-12). The day you’ll further reduce your use of Nicorette Gum. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 8 Nine weeks after you begin using Nicorette Gum, you will further reduce your nicotine intake by using one piece every four to eight hours. Place the Step 3 sticker on this date (the ﬁ rst day of week ten). For the next three weeks, you’ll use a piece of Nicorette Gum every four to eight hours. End of treatment: The day you’ll complete Nicorette Gum therapy. Nicorette Gum should not be used for longer than twelve weeks. Identify the date thirteen weeks after the date you chose in Step 1, and place the “EX-SMOKER” sticker on your calendar. Because smoking is an addiction, it is not easy to stop. After you’ve given up cigarettes, you will still have a strong urge to smoke. Plan ahead NOW for these times, so you’re not defeated in a moment of weakness. The following tips may help: • Keep the phone numbers of supportive friends and family members handy. • Keep a record of your quitting process. Track the number of Nicorette Gum pieces you use each day, and whether you feel a craving for cigarettes. In the event that PLAN AHEAD. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 9 you slip, immediately stop smoking and resume your quit attempt with the Nicorette Gum program. • Put together an Emergency Kit that includes items that will help take your mind off occasional urges to smoke. Include cinnamon gum or lemon drops to suck on, a relaxing CD, and something for your hands to play with, like a smooth rock, rubber band, or small metal balls. • Set aside some small rewards, like a new magazine or a gift certiﬁ cate from your favorite store, which you’ll “give” yourself after passing difﬁ cult hurdles. • Think now about the times when you most often want a cigarette, and then plan what else you might do instead of smoking. For instance, you might plan to take your coffee break in a new location, or take a walk right after dinner, so you won’t be tempted to smoke. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. the addictive part of cigarette smoke. Nicotine can cause side effects such as headache, nausea, upset stomach, and dizziness. If you are under 18 years of age, ask a doctor before use. Before you can use Nicorette Gum correctly, you have to prac- tice! That sounds silly, but it isn’t. Nicorette Gum isn’t like ordinary chewing gum. It’s a medicine, and must be chewed a certain way to work right. Chewed like ordinary gum, Nicorette Gum won’t work well and Nicorette Gum’s sug- ar-free chewing pieces provide nicotine to your system – they work as a temporary aid to help you quit smoking by reducing nicotine withdrawal symptoms. Nicorette Gum provides a lower level of nicotine to your blood than ciga- rettes, and allows you to gradually do away with your body’s need for nicotine. Because Nicorette Gum does not contain the tar or carbon monoxide of cigarette smoke, it does not have the same health dangers as tobacco. However, it still delivers nicotine, 10 HOW NICOrette gum works. HOW To Use NICOrette gum. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. can cause side effects. An overdose can occur if you chew more than one piece of Nicorette Gum at the same time, or if you chew many pieces one after another. Read all the following instructions before using Nicorette Gum. Refer to them often to make sure you’re using Nicorette Gum correctly. If you chew too fast, or do not chew correctly, you may get hiccups, heart- burn, or other stomach problems. Don’t eat or drink for 15 minutes before using Nicorette Gum, or while chewing a piece. The effectiveness of Nicorette Gum may be reduced by some foods and drinks, such as 11 coffee, juices, wine or soft drinks. 1) Stop smoking completely before you start using Nicorette Gum. 2) To reduce craving and other withdrawal symptoms, use Nicorette Gum according to the dosage schedule on page 12. 3) Chew each Nicorette Gum piece very slowly several times. 4) Stop chewing when you notice a peppery taste, or a slight tingling in your mouth. (This usually happens after about 15 chews, but may vary from person to person.) Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 12 5) “PARK” the Nicorette Gum piece between your cheek and gum, and leave it there. 6) When the peppery taste or tingle is almost gone (in about a minute), start to chew a few times slowly again. When the taste or tingle returns, stop again. 7) Park the Nicorette Gum piece again (in a different place in your mouth). 8) Repeat steps 3 to 7 (chew, chew, park) until most of the nicotine is gone from the Nicorette Gum piece (usually happens in about half an hour; the peppery taste or tingle won’t return.) 9) Wrap the used Nicorette Gum piece in paper and throw away in the trash. To improve your chances of quitting, use at least 9 pieces of Nicorette Gum a day. If you experience strong or frequent cravings, you may use a second piece within the hour. However, do not continuously use one The following chart lists the recommended usage schedule for Nicorette Gum: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 piece every 1 piece every 1 piece every 1 to 2 hours 2 to 4 hours 4 to 8 hours DO NOT USE MORE THAN 24 PIECES PER DAY. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ENROLL NOW! A Personal Invitation to Join brought to you by ® ® ® Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda is a FREE custom-tailored plan to help you break your psychological addiction to smoking — while NICORETTE Gum ﬁ ghts the physical addiction. To get your plan, call toll free 1-800-770-0708 or visit us on the Web at www.committedquitters.com. Having a Plan Will Help You Quit To Enroll Call Now 1-800-770-0708 or enroll online at www.committedquitters.com ® ® ® Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHEN YOU CALL: You will be asked a few questions to understand YOU and YOUR speciﬁ c needs. AFTER YOU CALL: In a few days, you will receive your custom-tailored stop smoking plan. You will continue to receive personal, custom-tailored support — six times during the next twelve weeks. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Your Plan Will Contain: 12-week stop smoking plan Newsletter with stories from other successful quitters Motivational postcard Week 1 Week 2 Week 3 Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Materials are subject to change. More tips on quitting Congratulations Packet Award Certiﬁ cate Week 6 Week 9 Week 12 Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How To Survive the First Week: Quitting Tips 3. Stay active. Keep busy to take your mind off smoking. 4. Think positive! The ﬁ rst week is the toughest. Remind yourself that it will get easier. Use the sample of the Stop Smoking Plan (see next page) to get you through the ﬁ rst week until your materials arrive. 1. Control your physical cravings for nicotine. Use enough – You can greatly increase your chances for success by using at least 9 to 12 pieces every day when you start using Nicorette Gum. 2. Get rid of all signs that you ever smoked — ashtrays, matches and, of course, cigarettes. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Day Pieces Chewed Planning: Plan ahead. Note events here that will tempt you to smoke, and how you will deal with them. 1. _________ _______________________________________________________________ 2. _________ _______________________________________________________________ 3. _________ _______________________________________________________________ 4. _________ _______________________________________________________________ 5. _________ _______________________________________________________________ 6. _________ _______________________________________________________________ 7. _________ _______________________________________________________________ The toughest hurdle — your ﬁ rst week without cigarettes. Your craving for nicotine will be strongest during this ﬁ rst week. To deal with physical withdrawal, use Nicorette Gum properly. Follow the directions on your Nicorette Gum package. WEEK ONE CALENDAR ✁ If you have gone back to smoking, call 1-800-770-0708 to order relapse information. • Make sure you tell friends and family members that you quit. • Use enough Nicorette Gum — at least 9 to 12 pieces per day. • Stay active. Keep busy to take your mind off smoking. • When an urge to smoke strikes, take a few deep breaths and remind yourself how important quitting is to you. TIPS *Carry this calendar with you. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ©2011 GlaxoSmithKline The Committed Quitters ® program is a plan speciﬁ cally individualized for you. Call Between 7 am and 12 Midnight ET or enroll online 24 hours a day. (ONE PLAN PER CUSTOMER) NICORETTE and COMMITTED QUITTERS are registered trademarks, and associated logo designs and overall dress designs are trademarks owned and/or licensed to the GlaxoSmithKline group of companies. Read and follow label directions Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 13 piece after another, since this may cause you hiccups, heartburn, nausea or other side effects. The goal of using Nicorette Gum is to slowly reduce your dependence on nico- tine. The schedule for using Nicorette Gum will help you reduce your nicotine craving gradually as you reduce and then stop your use of Nicorette Gum. Here are some tips to help you cut back during each step and then stop using Nicorette Gum: HOW to reduce your nicorette GUM usage. • After a while, start chewing each Nicorette Gum piece for only 10 to 15 minutes, instead of half an hour. Then, gradually begin to reduce the number of pieces used. • Or, try chewing each piece for longer than half an hour, but reduce the number of pieces you use each day. • Substitute ordinary chewing gum for some of the Nicorette Gum pieces you would normally use. Increase the number of pieces of ordinary gum as you cut back on the Nicorette Gum pieces. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 14 • Check how well you’ve reduced your daily usage of Nicorette Gum in Weeks 10 to 12. You should only be using about 3 to 5 pieces a day. Get ready to stop. STOP USING NICORETTE GUM AT THE END OF WEEK 12. The following tips may help you with stopping Nicorette Gum at the end of 12 weeks. • Set a stop date. • Use the same number of pieces of confectionery gum or mints as you were using Nicorette Gum per day. At the times when you have an urge to use Nicorette Gum, use a strong ﬂ avored gum or mint such as cinnamon or peppermint. • Reduce the number of pieces of gum or mints you use by one piece per day until you do not need to use any gum or mints. Talk to your doctor if you: • still feel the need to use Nicorette Gum at the end of week 12 • start using Nicorette Gum again after stopping • start smoking again Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 15 Within the ﬁ rst few weeks of giving up smoking, you may be tempted to smoke for pleasure, particularly after completing a difﬁ cult task, or at a party or bar. Here are some tips to help get you through the important ﬁ rst stages of becoming a non-smoker: On Your Quit Date: • Ask your family, friends and co-workers to support you in your efforts to stop smoking. TIPS TO MAKE QUITTING EASIER. • Throw away all your cigarettes, matches, lighters, ashtrays, etc. • Keep busy on your quit day. Exercise. Go to a movie. Take a walk. Get together with friends. • Figure out how much money you’ll save by not smoking. Most ex-smokers can save more than $1,000 a year. • Write down what you will do with the money you save. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 16 • Know your high risk situations and plan ahead how you will deal with them. • Keep Nicorette Gum near your bed, so you’ll be prepared for any nicotine cravings when you wake up in the morning. • Visit your dentist and have your teeth cleaned to get rid of the tobacco stains. Right after Quitting: • During the ﬁ rst few days after you’ve stopped smoking, spend as much time as possible at places where smoking is not allowed. • Drink large quantities of water and fruit juices. • Try to avoid alcohol, coffee and other beverages you associate with smoking. • Remember that temporary urges to smoke will pass, even if you don’t smoke a cigarette. • Keep your hands busy with something like a pencil or a paper clip. • Find other activities which help you relax without cigarettes. • Swim, jog, take a walk, play basketball. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 17 stop smoking, you might feel edgy and nervous and have trouble concentrating. You might get headaches, feel dizzy and a little out of sorts, feel sweaty or have stomach upsets. You might even have trouble sleeping at ﬁ rst. These are typical withdrawal symptoms that will go away with time. Your smoker’s cough will get worse before it gets better. But don’t worry, that’s a good sign. Coughing helps clear the tar deposits out of your lungs. what to expect. • Don’t worry too much about gaining weight. Watch what you eat, take time for daily exercise, and change your eating habits if you need to. • Laughter helps. Watch or read something funny. Your body is now coming back into balance. During the ﬁ rst few days after you Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 18 After A Week Or Two. By now you should be feeling more conﬁ dent that you can handle those smoking urges. Many of your withdrawal symptoms have left by now, and you should be noticing some positive signs: less coughing, better breathing and an improved sense of taste and smell, to name a few. After A Month. You probably have the urge to smoke much less often now. But urges may still occur, and when they do, they are likely to be powerful ones that come out of nowhere. Don’t let them catch you off guard. Plan ahead for these difﬁ cult times. Concentrate on the ways non-smokers are more attractive than smokers. Their skin is less likely to wrinkle. Their teeth are whiter, cleaner. Their breath is fresher. Their hair and clothes smell better. That cough that seems to make even a laugh sound more like a rattle is a thing of the past. Their children and others around them are healthier, too. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 19 What To Do About Relapse. What should you do if you slip and start smoking again? The answer is simple. A lapse of one or two or even a few cigarettes has not spoiled your efforts! Discard your cigarettes, forgive yourself and try again. If you start smoking again, keep your box of Nicorette Gum for your next quit attempt. If you have taken up regular smoking again, don’t be discouraged. Research shows that the best thing you can do is to try again. The important thing is to learn from your last attempt. • Admit that you’ve slipped, but don’t treat yourself as a failure. • Try to identify the “trigger” that caused you to slip, and prepare a better plan for dealing with this problem next time. • Talk positively to yourself – tell yourself that you have learned something from this experience. • Make sure you used Nicorette Gum correctly over the full 12 weeks to reduce your craving for nicotine. • Remember that it takes practice to do Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 20 anything, and quitting smoking is no exception. Once you’ve stopped smoking, take a second and pat yourself on your back. Now do it again. You deserve it. Remember now why you decided to stop smoking in the ﬁ rst place. Look at your list of reasons. Read them again. And smile. Now think about all the money you are saving and what you’ll do with it. All the non-smoking places you can go, and what you might do there. WHEN THE struggle IS over. All those years you may have added to your life, and what you’ll do with them. Remember that temptation may not be gone forever. However, the hard part is behind you so look forward with a positive attitude, and enjoy your new life as a non-smoker. QUESTIONS & ANSWERS. 1. How will I feel when I stop smoking and start using Nicorette Gum? You’ll need to prepare yourself for some nicotine withdrawal symptoms. These begin almost immediately after you stop Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 21 smoking, and are usually at their worst during the ﬁ rst three or four days. Understand that any of the following is possible: • craving for cigarettes • anxiety, irritability, restlessness, mood changes, nervousness • drowsiness • trouble concentrating • increased appetite and weight gain • headaches, muscular pain, constipation, fatigue. Nicorette Gum can help provide relief from withdrawal symptoms such as irritability and nervousness, as well as the craving for nicotine you used to satisfy by having a cigarette. 2. Is Nicorette Gum just substituting one form of nicotine for another? Nicorette Gum does contain nicotine. The purpose of Nicorette Gum is to provide you with enough nicotine to help control the physical withdrawal symptoms so you can deal with the mental aspects of quitting. Dur- ing the 12 week program, you will gradually Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 22 reduce your nicotine intake by switching to fewer pieces each day. Remember, don’t use Nicorette Gum together with nicotine patches or other nicotine containing products. 3. Can I be hurt by using Nicorette Gum? For most adults, the amount of nicotine in the gum is less than from smoking. Some people will be sensitive to even this amount of nicotine and should not use this product without advice from their doctor (see page 5). Because Nicorette Gum is a gum-based product, chewing it can cause dental ﬁ llings to loosen and aggravate other mouth, tooth and jaw problems. Nicorette Gum can also cause hiccups, heartburn and other stomach problems especially if chewed too quickly or not chewed correctly. 4. Will I gain weight? Many people do tend to gain a few pounds the ﬁ rst 8-10 weeks after they stop smok- ing. This is a very small price to pay for the enormous gains that you will make in your overall health and attractiveness. If you Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. 23 continue to gain weight after the ﬁ rst two months, try to analyze what you’re doing differently. Reduce your fat intake, choose healthy snacks, and increase your physical activity to burn off the extra calories. 5. Is Nicorette Gum more expensive than smoking? The total cost of Nicorette Gum for the twelve week program is about equal to what a person who smokes one and a half packs of cigarettes a day would spend on cigarettes for the same period of time. Also, use of Nicorette Gum is only a short-term cost, while the cost of smoking is a long-term cost, because of the health problems smoking causes. 6. What if I slip up? Discard your cigarettes, forgive yourself and then get back on track. Don’t consider yourself a failure or punish yourself. In fact, people who have already tried to quit are more likely to be successful the next time. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda GOOD LUCK! Recommended dosage schedule for Nicorette Gum: STEP 1 STEP 2 STEP 3 weeks 1 to 6 1 piece every 1 to 2 hours weeks 7 to 9 1 piece every 2 to 4 hours weeks 10 to 12 1 piece every 4 to 8 hours 00000XX Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. My most important reasons to quit smoking are: WALLET CARD Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Copyright ©2011 GlaxoSmithKline Consumer Healthcare, L.P. WHERE TO CALL FOR HELP WALLET CARD American Lung Association 1-800-586-4872 American Cancer Society 1-800-227-2345 American Heart Association 1-800-242-8721 Reference ID: 3084533 Reference ID: 3087459 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:39.505196	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018612s061_020066s042lbl.pdf', 'application_number': 20066, 'submission_type': 'SUPPL ', 'submission_number': 42}
12,175	1 2 EC-NAPROSYN® (naproxen delayed-release tablets) 3 NAPROSYN® (naproxen tablets) 4 ANAPROX®/ANAPROX® DS (naproxen sodium tablets) 5 NAPROSYN® (naproxen suspension) Roche Logo 6 Rx only Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). • Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). 7 DESCRIPTION 8 Naproxen is a proprionic acid derivative related to the arylacetic acid group of 9 nonsteroidal anti-inflammatory drugs. 10 The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α 11 methyl-2-naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2 12 naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen 13 sodium have the following structures, respectively: Chemical Structure 15 Naproxen has a molecular weight of 230.26 and a molecular formula of 16 C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a 17 molecular formula of C14H13NaO3. 18 Naproxen is an odorless, white to off-white crystalline substance. It is lipid 19 soluble, practically insoluble in water at low pH and freely soluble in water at 20 high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 21 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely 22 soluble in water at neutral pH. 23 NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 24 mg of naproxen, pink tablets containing 375 mg of naproxen and yellow 25 tablets containing 500 mg of naproxen for oral administration. The inactive 26 ingredients are croscarmellose sodium, iron oxides, povidone and magnesium 27 stearate. 28 EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric 29 coated white tablets containing 375 mg of naproxen and 500 mg of naproxen 30 for oral administration. The inactive ingredients are croscarmellose sodium, 31 povidone and magnesium stearate. The enteric coating dispersion contains 32 methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and 33 purified water. The dissolution of this enteric-coated naproxen tablet is pH 34 dependent with rapid dissolution above pH 6. There is no dissolution below 35 pH 4. 36 ANAPROX (naproxen sodium tablets) is available as blue tablets containing 37 275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is 38 available as dark blue tablets containing 550 mg of naproxen sodium for oral 39 administration. The inactive ingredients are magnesium stearate, 40 microcrystalline cellulose, povidone and talc. The coating suspension for the 41 ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, 42 Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The 43 coating suspension for the ANAPROX DS 550 mg tablet may contain 44 hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene 45 glycol 8000 or Opadry YS-1-4216. 46 NAPROSYN (naproxen suspension) is available as a light orange-colored 47 opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle 48 containing sucrose, magnesium aluminum silicate, sorbitol solution and 49 sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C 50 Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified 51 water. The pH of the suspension ranges from 2.2 to 3.7. 52 CLINICAL PHARMACOLOGY 53 Pharmacodynamics 54 Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic 55 and antipyretic properties. The sodium salt of naproxen has been developed as 56 a more rapidly absorbed formulation of naproxen for use as an analgesic. The 57 mechanism of action of the naproxen anion, like that of other NSAIDs, is not 58 completely understood but may be related to prostaglandin synthetase 59 inhibition. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 60 Pharmacokinetics 61 Naproxen and naproxen sodium are rapidly and completely absorbed from the 62 gastrointestinal tract with an in vivo bioavailability of 95%. The different 63 dosage forms of NAPROSYN are bioequivalent in terms of extent of 64 absorption (AUC) and peak concentration (Cmax); however, the products do 65 differ in their pattern of absorption. These differences between naproxen 66 products are related to both the chemical form of naproxen used and its 67 formulation. Even with the observed differences in pattern of absorption, the 68 elimination half-life of naproxen is unchanged across products ranging from 69 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and 70 the degree of naproxen accumulation is consistent with this half-life. This 71 suggests that the differences in pattern of release play only a negligible role in 72 the attainment of steady-state plasma levels. 73 Absorption 74 Immediate Release 75 After administration of NAPROSYN tablets, peak plasma levels are attained 76 in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels 77 are attained in 1 to 2 hours. The difference in rates between the two products 78 is due to the increased aqueous solubility of the sodium salt of naproxen used 79 in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN 80 Suspension are attained in 1 to 4 hours. 81 Delayed Release 82 EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier 83 to disintegration in the acidic environment of the stomach and to lose integrity 84 in the more neutral environment of the small intestine. The enteric polymer 85 coating selected for EC-NAPROSYN dissolves above pH 6. When EC 86 NAPROSYN was given to fasted subjects, peak plasma levels were attained 87 about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo 88 study in man using radiolabeled EC-NAPROSYN tablets demonstrated that 89 EC-NAPROSYN dissolves primarily in the small intestine rather than in the 90 stomach, so the absorption of the drug is delayed until the stomach is emptied. 91 When EC-NAPROSYN and NAPROSYN were given to fasted subjects 92 (n=24) in a crossover study following 1 week of dosing, differences in time to 93 peak plasma levels (Tmax) were observed, but there were no differences in total 94 absorption as measured by Cmax and AUC: 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) Tmax (hours) AUC0–12 hr (µg·hr/mL) 94.9 (18%) 4 (39%) 845 (20%) 97.4 (13%) 1.9 (61%) 767 (15%) 95 Mean value (coefficient of variation) 96 Antacid Effects 97 When EC-NAPROSYN was given as a single dose with antacid (54 mEq 98 buffering capacity), the peak plasma levels of naproxen were unchanged, but 99 the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with 100 antacid 5 hours), although not significantly. 101 Food Effects 102 When EC-NAPROSYN was given as a single dose with food, peak plasma 103 levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). 104 Residence time in the small intestine until disintegration was independent of 105 food intake. The presence of food prolonged the time the tablets remained in 106 the stomach, time to first detectable serum naproxen levels, and time to 107 maximal naproxen levels (Tmax), but did not affect peak naproxen levels 108 (Cmax). 109 Distribution 110 Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels 111 naproxen is greater than 99% albumin-bound. At doses of naproxen greater 112 than 500 mg/day there is less than proportional increase in plasma levels due 113 to an increase in clearance caused by saturation of plasma protein binding at 114 higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 115 1500 mg daily doses of naproxen, respectively). The naproxen anion has been 116 found in the milk of lactating women at a concentration equivalent to 117 approximately 1% of maximum naproxen concentration in plasma (see 118 PRECAUTIONS: Nursing Mothers). 119 Metabolism 120 Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, 121 and both parent and metabolites do not induce metabolizing enzymes. Both 122 naproxen and 6-0-desmethyl naproxen are further metabolized to their 123 respective acylglucuronide conjugated metabolites. 124 Excretion 125 The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the 126 naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 127 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 128 half-life of the naproxen anion in humans ranges from 12 to 17 hours. The 129 corresponding half-lives of both naproxen’s metabolites and conjugates are 130 shorter than 12 hours, and their rates of excretion have been found to coincide 131 closely with the rate of naproxen disappearance from the plasma. Small 132 amounts, 3% or less of the administered dose, are excreted in the feces. In 133 patients with renal failure metabolites may accumulate (see WARNINGS: 134 Renal Effects). 135 Special Populations 136 Pediatric Patients 137 In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels 138 following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND 139 ADMINISTRATION) were found to be similar to those found in normal 140 adults following a 500 mg dose. The terminal half-life appears to be similar in 141 pediatric and adult patients. Pharmacokinetic studies of naproxen were not 142 performed in pediatric patients younger than 5 years of age. Pharmacokinetic 143 parameters appear to be similar following administration of naproxen 144 suspension or tablets in pediatric patients. EC-NAPROSYN has not been 145 studied in subjects under the age of 18. 146 Geriatric Patients 147 Studies indicate that although total plasma concentration of naproxen is 148 unchanged, the unbound plasma fraction of naproxen is increased in the 149 elderly, although the unbound fraction is <1% of the total naproxen 150 concentration. Unbound trough naproxen concentrations in elderly subjects 151 have been reported to range from 0.12% to 0.19% of total naproxen 152 concentration, compared with 0.05% to 0.075% in younger subjects. The 153 clinical significance of this finding is unclear, although it is possible that the 154 increase in free naproxen concentration could be associated with an increase 155 in the rate of adverse events per a given dosage in some elderly patients. 156 Race 157 Pharmacokinetic differences due to race have not been studied. 158 Hepatic Insufficiency 159 Naproxen pharmacokinetics has not been determined in subjects with hepatic 160 insufficiency. 161 Renal Insufficiency 162 Naproxen pharmacokinetics has not been determined in subjects with renal 163 insufficiency. Given that naproxen, its metabolites and conjugates are 164 primarily excreted by the kidney, the potential exists for naproxen metabolites 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 165 to accumulate in the presence of renal insufficiency. Elimination of naproxen 166 is decreased in patients with severe renal impairment. Naproxen-containing 167 products are not recommended for use in patients with moderate to severe and 168 severe renal impairment (creatinine clearance <30 mL/min) (see 169 WARNINGS: Renal Effects). 170 CLINICAL STUDIES 171 General Information 172 Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, 173 juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute 174 gout. Improvement in patients treated for rheumatoid arthritis was 175 demonstrated by a reduction in joint swelling, a reduction in duration of 176 morning stiffness, a reduction in disease activity as assessed by both the 177 investigator and patient, and by increased mobility as demonstrated by a 178 reduction in walking time. Generally, response to naproxen has not been 179 found to be dependent on age, sex, severity or duration of rheumatoid arthritis. 180 In patients with osteoarthritis, the therapeutic action of naproxen has been 181 shown by a reduction in joint pain or tenderness, an increase in range of 182 motion in knee joints, increased mobility as demonstrated by a reduction in 183 walking time, and improvement in capacity to perform activities of daily 184 living impaired by the disease. 185 In a clinical trial comparing standard formulations of naproxen 375 mg bid 186 (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group 187 terminated prematurely because of adverse events. Nineteen patients in the 188 1500 mg group terminated prematurely because of adverse events. Most of 189 these adverse events were gastrointestinal events. 190 In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and 191 juvenile arthritis, naproxen has been shown to be comparable to aspirin and 192 indomethacin in controlling the aforementioned measures of disease activity, 193 but the frequency and severity of the milder gastrointestinal adverse effects 194 (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, 195 dizziness, lightheadedness) were less in naproxen-treated patients than in 196 those treated with aspirin or indomethacin. 197 In patients with ankylosing spondylitis, naproxen has been shown to decrease 198 night pain, morning stiffness and pain at rest. In double-blind studies the drug 199 was shown to be as effective as aspirin, but with fewer side effects. 200 In patients with acute gout, a favorable response to naproxen was shown by 201 significant clearing of inflammatory changes (eg, decrease in swelling, heat) 202 within 24 to 48 hours, as well as by relief of pain and tenderness. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 203 Naproxen has been studied in patients with mild to moderate pain secondary 204 to postoperative, orthopedic, postpartum episiotomy and uterine contraction 205 pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in 206 patients taking naproxen and within 30 minutes in patients taking naproxen 207 sodium. Analgesic effect was shown by such measures as reduction of pain 208 intensity scores, increase in pain relief scores, decrease in numbers of patients 209 requiring additional analgesic medication, and delay in time to remedication. 210 The analgesic effect has been found to last for up to 12 hours. 211 Naproxen may be used safely in combination with gold salts and/or 212 corticosteroids; however, in controlled clinical trials, when added to the 213 regimen of patients receiving corticosteroids, it did not appear to cause greater 214 improvement over that seen with corticosteroids alone. Whether naproxen has 215 a “steroid-sparing” effect has not been adequately studied. When added to the 216 regimen of patients receiving gold salts, naproxen did result in greater 217 improvement. Its use in combination with salicylates is not recommended 218 because there is evidence that aspirin increases the rate of excretion of 219 naproxen and data are inadequate to demonstrate that naproxen and aspirin 220 produce greater improvement over that achieved with aspirin alone. In 221 addition, as with other NSAIDs, the combination may result in higher 222 frequency of adverse events than demonstrated for either product alone. 223 In 51Cr blood loss and gastroscopy studies with normal volunteers, daily 224 administration of 1000 mg of naproxen as 1000 mg of NAPROSYN 225 (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been 226 demonstrated to cause statistically significantly less gastric bleeding and 227 erosion than 3250 mg of aspirin. 228 Three 6-week, double-blind, multicenter studies with EC-NAPROSYN 229 (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, 230 n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, 231 including 355 rheumatoid arthritis and osteoarthritis patients who had a recent 232 history of NSAID-related GI symptoms. These studies indicated that EC 233 NAPROSYN and NAPROSYN showed no significant differences in efficacy 234 or safety and had similar prevalence of minor GI complaints. Individual 235 patients, however, may find one formulation preferable to the other. 236 Five hundred and fifty-three patients received EC-NAPROSYN during long 237 term open-label trials (mean length of treatment was 159 days). The rates for 238 clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been 239 historically reported for long-term NSAID use. 240 Geriatric Patients 241 The hepatic and renal tolerability of long-term naproxen administration was 242 studied in two double-blind clinical trials involving 586 patients. Of the 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 243 patients studied, 98 patients were age 65 and older and 10 of the 98 patients 244 were age 75 and older. Naproxen was administered at doses of 375 mg twice 245 daily or 750 mg twice daily for up to 6 months. Transient abnormalities of 246 laboratory tests assessing hepatic and renal function were noted in some 247 patients, although there were no differences noted in the occurrence of 248 abnormal values among different age groups. 249 INDICATIONS AND USAGE 250 Carefully consider the potential benefits and risks of NAPROSYN, EC 251 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and 252 other treatment options before deciding to use NAPROSYN, EC 253 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use 254 the lowest effective dose for the shortest duration consistent with individual 255 patient treatment goals (see WARNINGS). 256 Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 257 NAPROSYN Suspension is indicated: 258 • For the relief of the signs and symptoms of rheumatoid arthritis 259 • For the relief of the signs and symptoms of osteoarthritis 260 • For the relief of the signs and symptoms of ankylosing spondylitis 261 • For the relief of the signs and symptoms of juvenile arthritis 262 Naproxen as NAPROSYN Suspension is recommended for juvenile 263 rheumatoid arthritis in order to obtain the maximum dosage flexibility based 264 on the patient’s weight. 265 Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN 266 Suspension is also indicated: 267 • For relief of the signs and symptoms of tendonitis 268 • For relief of the signs and symptoms of bursitis 269 • For relief of the signs and symptoms of acute gout 270 • For the management of pain 271 • For the management of primary dysmenorrhea 272 EC-NAPROSYN is not recommended for initial treatment of acute pain 273 because the absorption of naproxen is delayed compared to absorption from 274 other naproxen-containing products (see CLINICAL PHARMACOLOGY 275 and DOSAGE AND ADMINISTRATION). 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 276 CONTRAINDICATIONS 277 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 278 NAPROSYN Suspension are contraindicated in patients with known 279 hypersensitivity to naproxen and naproxen sodium. 280 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 281 NAPROSYN Suspension should not be given to patients who have 282 experienced asthma, urticaria, or allergic-type reactions after taking aspirin or 283 other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs 284 have been reported in such patients (see WARNINGS: Anaphylactoid 285 Reactions and PRECAUTIONS: Preexisting Asthma). 286 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 287 NAPROSYN Suspension are contraindicated for the treatment of peri 288 operative pain in the setting of coronary artery bypass graft (CABG) surgery 289 (see WARNINGS). 290 WARNINGS 291 CARDIOVASCULAR EFFECTS 292 Cardiovascular Thrombotic Events 293 Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 294 three years duration have shown an increased risk of serious cardiovascular 295 (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. 296 All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. 297 Patients with known CV disease or risk factors for CV disease may be at 298 greater risk. To minimize the potential risk for an adverse CV event in patients 299 treated with an NSAID, the lowest effective dose should be used for the 300 shortest duration possible. Physicians and patients should remain alert for the 301 development of such events, even in the absence of previous CV symptoms. 302 Patients should be informed about the signs and/or symptoms of serious CV 303 events and the steps to take if they occur. 304 There is no consistent evidence that concurrent use of aspirin mitigates the 305 increased risk of serious CV thrombotic events associated with NSAID use. 306 The concurrent use of aspirin and an NSAID does increase the risk of serious 307 GI events (see Gastrointestinal Effects – Risk of Ulceration, Bleeding, and 308 Perforation). 309 Two large, controlled, clinical trials of a COX-2 selective NSAID for the 310 treatment of pain in the first 10-14 days following CABG surgery found an 311 increased incidence of myocardial infarction and stroke (see 312 CONTRAINDICATIONS). 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 313 Hypertension 314 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 315 ANAPROX DS and NAPROSYN Suspension, can lead to onset of new 316 hypertension or worsening of pre-existing hypertension, either of which may 317 contribute to the increased incidence of CV events. Patients taking thiazides or 318 loop diuretics may have impaired response to these therapies when taking 319 NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 320 ANAPROX DS and NAPROSYN Suspension, should be used with caution in 321 patients with hypertension. Blood pressure (BP) should be monitored closely 322 during the initiation of NSAID treatment and throughout the course of 323 therapy. 324 Congestive Heart Failure and Edema 325 Fluid retention, edema, and peripheral edema have been observed in some 326 patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, 327 ANAPROX DS and NAPROSYN Suspension should be used with caution in 328 patients with fluid retention, hypertension, or heart failure. Since each 329 ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium 330 (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of 331 NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of 332 naproxen) of sodium, this should be considered in patients whose overall 333 intake of sodium must be severely restricted. 334 Gastrointestinal Effects – Risk of Ulceration, Bleeding, and 335 Perforation 336 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 337 ANAPROX DS and NAPROSYN Suspension, can cause serious 338 gastrointestinal (GI) adverse events including inflammation, bleeding, 339 ulceration, and perforation of the stomach, small intestine, or large intestine, 340 which can be fatal. 341 These serious adverse events can occur at any time, with or without warning 342 symptoms, in patients treated with NSAIDs. Only one in five patients, who 343 develop a serious upper GI adverse event on NSAID therapy, is symptomatic. 344 Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in 345 approximately 1% of patients treated for 3-6 months, and in about 2-4% of 346 patients treated for one year. These trends continue with longer duration of 347 use, increasing the likelihood of developing a serious GI event at some time 348 during the course of therapy. However, even short-term therapy is not without 349 risk. The utility of periodic laboratory monitoring has not been demonstrated, 350 nor has it been adequately assessed. Only 1 in 5 patients who develop a 351 serious upper GI adverse event on NSAID therapy is symptomatic. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 352 NSAIDs should be prescribed with extreme caution in those with a prior 353 history of ulcer disease or gastrointestinal bleeding. Patients with a prior 354 history of peptic ulcer disease and/or gastrointestinal bleeding who use 355 NSAIDs have a greater than 10-fold increased risk for developing a GI bleed 356 compared to patients with neither of these risk factors. Other factors that 357 increase the risk for GI bleeding in patients treated with NSAIDs include 358 concomitant use of oral corticosteroids or anticoagulants, longer duration of 359 NSAID therapy, smoking, use of alcohol, older age, and poor general health 360 status. Most spontaneous reports of fatal GI events are in elderly or debilitated 361 patients and therefore, special care should be taken in treating this population. 362 To minimize the potential risk for an adverse GI event in patients treated with 363 an NSAID, the lowest effective dose should be used for the shortest possible 364 duration. Patients and physicians should remain alert for signs and symptoms 365 of GI ulceration and bleeding during NSAID therapy and promptly initiate 366 additional evaluation and treatment if a serious GI adverse event is suspected. 367 This should include discontinuation of the NSAID until a serious GI adverse 368 event is ruled out. For high risk patients, alternate therapies that do not 369 involve NSAIDs should be considered. 370 Epidemiological studies, both of the case-control and cohort design, have 371 demonstrated an association between use of psychotropic drugs that interfere 372 with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. 373 In two studies, concurrent use of an NSAID or aspirin potentiated the risk of 374 bleeding (see PRECAUTIONS: Drug Interactions). Although these studies 375 focused on upper gastrointestinal bleeding, there is reason to believe that 376 bleeding at other sites may be similarly potentiated. 377 NSAIDs should be given with care to patients with a history of inflammatory 378 bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be 379 exacerbated. 380 Renal Effects 381 Long-term administration of NSAIDs has resulted in renal papillary necrosis 382 and other renal injury. Renal toxicity has also been seen in patients in whom 383 renal prostaglandins have a compensatory role in the maintenance of renal 384 perfusion. In these patients, administration of a nonsteroidal 385 anti-inflammatory drug may cause a dose-dependent reduction in 386 prostaglandin formation and, secondarily, in renal blood flow, which may 387 precipitate overt renal decompensation. Patients at greatest risk of this 388 reaction are those with impaired renal function, hypovolemia, heart failure, 389 liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, 390 and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug 391 therapy is usually followed by recovery to the pretreatment state (see 392 WARNINGS: Advanced Renal Disease). 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 393 Advanced Renal Disease 394 No information is available from controlled clinical studies regarding the use 395 of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 396 NAPROSYN Suspension in patients with advanced renal disease. Therefore, 397 treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS 398 and NAPROSYN Suspension is not recommended in these patients with 399 advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, 400 ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close 401 monitoring of the patient’s renal function is advisable. 402 Anaphylactoid Reactions 403 As with other NSAIDs, anaphylactoid reactions may occur in patients without 404 known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX, 405 ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC 406 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension 407 should not be given to patients with the aspirin triad. This symptom complex 408 typically occurs in asthmatic patients who experience rhinitis with or without 409 nasal polyps, or who exhibit severe, potentially fatal bronchospasm after 410 taking aspirin or other NSAIDs (see CONTRAINDICATIONS and 411 PRECAUTIONS: Preexisting Asthma). Emergency help should be sought 412 in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like 413 anaphylaxis, may have a fatal outcome. 414 Skin Reactions 415 NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, 416 ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse 417 events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and 418 toxic epidermal necrolysis (TEN), which can be fatal. These serious events 419 may occur without warning. Patients should be informed about the signs and 420 symptoms of serious skin manifestations and use of the drug should be 421 discontinued at the first appearance of skin rash or any other sign of 422 hypersensitivity. 423 Pregnancy 424 In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, 425 ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided 426 because it may cause premature closure of the ductus arteriosus. 427 PRECAUTIONS 428 General 429 Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, 430 ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 431 other naproxen products should not be used concomitantly since they all 432 circulate in the plasma as the naproxen anion. 433 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 434 NAPROSYN Suspension cannot be expected to substitute for corticosteroids 435 or to treat corticosteroid insufficiency. Abrupt discontinuation of 436 corticosteroids may lead to disease exacerbation. Patients on prolonged 437 corticosteroid therapy should have their therapy tapered slowly if a decision is 438 made to discontinue corticosteroids and the patient should be observed closely 439 for any evidence of adverse effects, including adrenal insufficiency and 440 exacerbation of symptoms of arthritis. 441 Patients with initial hemoglobin values of 10 g or less who are to receive long 442 term therapy should have hemoglobin values determined periodically. 443 The pharmacological activity of NAPROSYN, EC-NAPROSYN, 444 ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever 445 and inflammation may diminish the utility of these diagnostic signs in 446 detecting complications of presumed noninfectious, noninflammatory painful 447 conditions. 448 Because of adverse eye findings in animal studies with drugs of this class, it is 449 recommended that ophthalmic studies be carried out if any change or 450 disturbance in vision occurs. 451 Hepatic Effects 452 Borderline elevations of one or more liver tests may occur in up to 15% of 453 patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, 454 ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic 455 abnormalities may be the result of hypersensitivity rather than direct toxicity. 456 These laboratory abnormalities may progress, may remain essentially 457 unchanged, or may be transient with continued therapy. The SGPT (ALT) test 458 is probably the most sensitive indicator of liver dysfunction. Notable 459 elevations of ALT or AST (approximately three or more times the upper limit 460 of normal) have been reported in approximately 1% of patients in clinical 461 trials with NSAIDs. In addition, rare cases of severe hepatic reactions, 462 including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic 463 failure, some of them with fatal outcomes have been reported. 464 A patient with symptoms and/or signs suggesting liver dysfunction, or in 465 whom an abnormal liver test has occurred, should be evaluated for evidence 466 of the development of more severe hepatic reaction while on therapy with 467 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 468 NAPROSYN Suspension. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 469 If clinical signs and symptoms consistent with liver disease develop, or if 470 systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC 471 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension 472 should be discontinued. 473 Chronic alcoholic liver disease and probably other diseases with decreased or 474 abnormal plasma proteins (albumin) reduce the total plasma concentration of 475 naproxen, but the plasma concentration of unbound naproxen is increased. 476 Caution is advised when high doses are required and some adjustment of 477 dosage may be required in these patients. It is prudent to use the lowest 478 effective dose. 479 Hematological Effects 480 Anemia is sometimes seen in patients receiving NSAIDs, including 481 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 482 NAPROSYN Suspension. This may be due to fluid retention, occult or gross 483 GI blood loss, or an incompletely described effect upon erythropoiesis. 484 Patients on long-term treatment with NSAIDs, including NAPROSYN, EC 485 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, 486 should have their hemoglobin or hematocrit checked if they exhibit any signs 487 or symptoms of anemia. 488 NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding 489 time in some patients. Unlike aspirin, their effect on platelet function is 490 quantitatively less, of shorter duration, and reversible. Patients receiving either 491 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or 492 NAPROSYN Suspension who may be adversely affected by alterations in 493 platelet function, such as those with coagulation disorders or patients 494 receiving anticoagulants, should be carefully monitored. 495 Preexisting Asthma 496 Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in 497 patients with aspirin-sensitive asthma has been associated with severe 498 bronchospasm, which can be fatal. Since cross reactivity, including 499 bronchospasm, between aspirin and other nonsteroidal anti-inflammatory 500 drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC 501 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension 502 should not be administered to patients with this form of aspirin sensitivity and 503 should be used with caution in patients with preexisting asthma. 504 Information for Patients 505 Patients should be informed of the following information before initiating 506 therapy with an NSAID and periodically during the course of ongoing 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 507 therapy. Patients should also be encouraged to read the NSAID 508 Medication Guide that accompanies each prescription dispensed. 509 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 510 NAPROSYN Suspension, like other NSAIDs, may cause serious CV side 511 effects, such as MI or stroke, which may result in hospitalization and even 512 death. Although serious CV events can occur without warning symptoms, 513 patients should be alert for the signs and symptoms of chest pain, 514 shortness of breath, weakness, slurring of speech, and should ask for 515 medical advice when observing any indicative sign or symptoms. Patients 516 should be apprised of the importance of this follow-up (see WARNINGS: 517 Cardiovascular Effects). 518 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 519 NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort 520 and, rarely, serious GI side effects, such as ulcers and bleeding, which 521 may result in hospitalization and even death. Although serious GI tract 522 ulcerations and bleeding can occur without warning symptoms, patients 523 should be alert for the signs and symptoms of ulcerations and bleeding, 524 and should ask for medical advice when observing any indicative sign or 525 symptoms including epigastric pain, dyspepsia, melena, and hematemesis. 526 Patients should be apprised of the importance of this follow-up (see 527 WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, 528 and Perforation). 529 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 530 NAPROSYN Suspension, like other NSAIDs, can cause serious skin side 531 effects such as exfoliative dermatitis, SJS, and TEN, which may result in 532 hospitalizations and even death. Although serious skin reactions may 533 occur without warning, patients should be alert for the signs and 534 symptoms of skin rash and blisters, fever, or other signs of 535 hypersensitivity such as itching, and should ask for medical advice when 536 observing any indicative signs or symptoms. Patients should be advised to 537 stop the drug immediately if they develop any type of rash and contact 538 their physicians as soon as possible. 539 4. Patients should promptly report signs or symptoms of unexplained weight 540 gain or edema to their physicians. 541 5. Patients should be informed of the warning signs and symptoms of 542 hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper 543 quadrant tenderness, and “flu-like” symptoms). If these occur, patients 544 should be instructed to stop therapy and seek immediate medical therapy. 545 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, 546 difficulty breathing, swelling of the face or throat). If these occur, patients 547 should be instructed to seek immediate emergency help (see 548 WARNINGS). 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 549 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, 550 ANAPROX, ANAPROX DS and NAPROSYN Suspension should be 551 avoided because it may cause premature closure of the ductus arteriosus. 552 8. Caution should be exercised by patients whose activities require alertness 553 if they experience drowsiness, dizziness, vertigo or depression during 554 therapy with naproxen. 555 Laboratory Tests 556 Because serious GI tract ulcerations and bleeding can occur without warning 557 symptoms, physicians should monitor for signs or symptoms of GI bleeding. 558 Patients on long-term treatment with NSAIDs should have their CBC and a 559 chemistry profile checked periodically. If clinical signs and symptoms 560 consistent with liver or renal disease develop, systemic manifestations occur 561 (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, 562 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 563 NAPROSYN Suspension should be discontinued. 564 Drug Interactions 565 ACE-inhibitors 566 Reports suggest that NSAIDs may diminish the antihypertensive effect of 567 ACE-inhibitors. This interaction should be given consideration in patients 568 taking NSAIDs concomitantly with ACE-inhibitors. 569 Antacids and Sucralfate 570 Concomitant administration of some antacids (magnesium oxide or aluminum 571 hydroxide) and sucralfate can delay the absorption of naproxen. 572 Aspirin 573 When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX 574 DS or NAPROSYN Suspension is administered with aspirin, its protein 575 binding is reduced, although the clearance of free NAPROSYN, EC 576 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is 577 not altered. The clinical significance of this interaction is not known; 578 however, as with other NSAIDs, concomitant administration of naproxen and 579 naproxen sodium and aspirin is not generally recommended because of the 580 potential of increased adverse effects. 581 Cholestyramine 582 As with other NSAIDs, concomitant administration of cholestyramine can 583 delay the absorption of naproxen. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 584 Diuretics 585 Clinical studies, as well as postmarketing observations, have shown that 586 NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and 587 NAPROSYN Suspension can reduce the natriuretic effect of furosemide and 588 thiazides in some patients. This response has been attributed to inhibition of 589 renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the 590 patient should be observed closely for signs of renal failure (see 591 WARNINGS: Renal Effects), as well as to assure diuretic efficacy. 592 Lithium 593 NSAIDs have produced an elevation of plasma lithium levels and a reduction 594 in renal lithium clearance. The mean minimum lithium concentration 595 increased 15% and the renal clearance was decreased by approximately 20%. 596 These effects have been attributed to inhibition of renal prostaglandin 597 synthesis by the NSAID. Thus, when NSAIDs and lithium are administered 598 concurrently, subjects should be observed carefully for signs of lithium 599 toxicity. 600 Methotrexate 601 NSAIDs have been reported to competitively inhibit methotrexate 602 accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other 603 nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular 604 secretion of methotrexate in an animal model. This may indicate that they 605 could enhance the toxicity of methotrexate. Caution should be used when 606 NSAIDs are administered concomitantly with methotrexate. 607 Warfarin 608 The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that 609 users of both drugs together have a risk of serious GI bleeding higher than 610 users of either drug alone. No significant interactions have been observed in 611 clinical studies with naproxen and coumarin-type anticoagulants. However, 612 caution is advised since interactions have been seen with other nonsteroidal 613 agents of this class. The free fraction of warfarin may increase substantially in 614 some subjects and naproxen interferes with platelet function. 615 Selective Serotonin Reuptake Inhibitors (SSRIs) 616 There is an increased risk of gastrointestinal bleeding when selective serotonin 617 reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be 618 used when NSAIDs are administered concomitantly with SSRIs. 619 Other Information Concerning Drug Interactions 620 Naproxen is highly bound to plasma albumin; it thus has a theoretical 621 potential for interaction with other albumin-bound drugs such as coumarin 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 622 type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. 623 Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or 624 sulphonylurea should be observed for adjustment of dose if required. 625 Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the 626 antihypertensive effect of propranolol and other beta-blockers. 627 Probenecid given concurrently increases naproxen anion plasma levels and 628 extends its plasma half-life significantly. 629 Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive 630 antacid therapy, concomitant administration of EC-NAPROSYN is not 631 recommended. 632 Drug/Laboratory Test Interaction 633 Naproxen may decrease platelet aggregation and prolong bleeding time. This 634 effect should be kept in mind when bleeding times are determined. 635 The administration of naproxen may result in increased urinary values for 17 636 ketogenic steroids because of an interaction between the drug and/or its 637 metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy 638 corticosteroid measurements (Porter-Silber test) do not appear to be 639 artifactually altered, it is suggested that therapy with naproxen be temporarily 640 discontinued 72 hours before adrenal function tests are performed if the 641 Porter-Silber test is to be used. 642 Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic 643 acid (5HIAA). 644 Carcinogenesis 645 A 2-year study was performed in rats to evaluate the carcinogenic potential of 646 naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). 647 The maximum dose used was 0.28 times the systemic exposure to humans at 648 the recommended dose. No evidence of tumorigenicity was found. 649 Pregnancy 650 Teratogenic Effects 651 Pregnancy Category C 652 Reproduction studies have been performed in rats at 20 mg/kg/day 653 (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 654 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and 655 mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic 656 exposure) with no evidence of impaired fertility or harm to the fetus due to the 657 drug. However, animal reproduction studies are not always predictive of 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 658 human response. There are no adequate and well-controlled studies in 659 pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX 660 DS and NAPROSYN Suspension should be used in pregnancy only if the 661 potential benefit justifies the potential risk to the fetus. 662 Nonteratogenic Effects 663 There is some evidence to suggest that when inhibitors of prostaglandin 664 synthesis are used to delay preterm labor there is an increased risk of neonatal 665 complications such as necrotizing enterocolitis, patent ductus arteriosus and 666 intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay 667 parturition has been associated with persistent pulmonary hypertension, renal 668 dysfunction and abnormal prostaglandin E levels in preterm infants. Because 669 of the known effects of nonsteroidal anti-inflammatory drugs on the fetal 670 cardiovascular system (closure of ductus arteriosus), use during pregnancy 671 (particularly late pregnancy) should be avoided. 672 Labor and Delivery 673 In rat studies with NSAIDs, as with other drugs known to inhibit 674 prostaglandin synthesis, an increased incidence of dystocia, delayed 675 parturition, and decreased pup survival occurred. Naproxen-containing 676 products are not recommended in labor and delivery because, through its 677 prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal 678 circulation and inhibit uterine contractions, thus increasing the risk of uterine 679 hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, 680 ANAPROX DS and NAPROSYN Suspension on labor and delivery in 681 pregnant women are unknown. 682 Nursing Mothers 683 The naproxen anion has been found in the milk of lactating women at a 684 concentration equivalent to approximately 1% of maximum naproxen 685 concentration in plasma. Because of the possible adverse effects of 686 prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be 687 avoided. 688 Pediatric Use 689 Safety and effectiveness in pediatric patients below the age of 2 years have 690 not been established. Pediatric dosing recommendations for juvenile arthritis 691 are based on well-controlled studies (see DOSAGE AND 692 ADMINISTRATION). There are no adequate effectiveness or dose-response 693 data for other pediatric conditions, but the experience in juvenile arthritis and 694 other use experience have established that single doses of 2.5 to 5 mg/kg (as 695 naproxen suspension, see DOSAGE AND ADMINISTRATION), with total 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 696 daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients 697 over 2 years of age. 698 Geriatric Use 699 Studies indicate that although total plasma concentration of naproxen is 700 unchanged, the unbound plasma fraction of naproxen is increased in the 701 elderly. Caution is advised when high doses are required and some adjustment 702 of dosage may be required in elderly patients. As with other drugs used in the 703 elderly, it is prudent to use the lowest effective dose. 704 Experience indicates that geriatric patients may be particularly sensitive to 705 certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or 706 debilitated patients seem to tolerate peptic ulceration or bleeding less well 707 when these events do occur. Most spontaneous reports of fatal GI events are in 708 the geriatric population (see WARNINGS). 709 Naproxen is known to be substantially excreted by the kidney, and the risk of 710 toxic reactions to this drug may be greater in patients with impaired renal 711 function. Because elderly patients are more likely to have decreased renal 712 function, care should be taken in dose selection, and it may be useful to 713 monitor renal function. Geriatric patients may be at a greater risk for the 714 development of a form of renal toxicity precipitated by reduced prostaglandin 715 formation during administration of nonsteroidal anti-inflammatory drugs (see 716 WARNINGS: Renal Effects). 717 ADVERSE REACTIONS 718 Adverse reactions reported in controlled clinical trials in 960 patients treated 719 for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions 720 in patients treated chronically were reported 2 to 10 times more frequently 721 than they were in short-term studies in the 962 patients treated for mild to 722 moderate pain or for dysmenorrhea. The most frequent complaints reported 723 related to the gastrointestinal tract. 724 A clinical study found gastrointestinal reactions to be more frequent and more 725 severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen 726 compared to those taking 750 mg naproxen (see CLINICAL 727 PHARMACOLOGY). 728 In controlled clinical trials with about 80 pediatric patients and in well 729 monitored, open-label studies with about 400 pediatric patients with juvenile 730 arthritis treated with naproxen, the incidence of rash and prolonged bleeding 731 times were increased, the incidence of gastrointestinal and central nervous 732 system reactions were about the same, and the incidence of other reactions 733 were lower in pediatric patients than in adults. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 734 In patients taking naproxen in clinical trials, the most frequently reported 735 adverse experiences in approximately 1% to 10% of patients are: 736 Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, 737 nausea, constipation, diarrhea, dyspepsia, stomatitis 738 Central Nervous System: headache, dizziness, drowsiness, 739 lightheadedness, vertigo 740 Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, 741 purpura 742 Special Senses: tinnitus, visual disturbances, hearing disturbances 743 Cardiovascular: edema, palpitations 744 General: dyspnea, thirst 745 Incidence of reported reaction between 3% and 9%. Those reactions 746 occurring in less than 3% of the patients are unmarked. 747 In patients taking NSAIDs, the following adverse experiences have also been 748 reported in approximately 1% to 10% of patients. 749 Gastrointestinal (GI) Experiences, including: flatulence, gross 750 bleeding/perforation, GI ulcers (gastric/duodenal), vomiting 751 General: abnormal renal function, anemia, elevated liver enzymes, increased 752 bleeding time, rashes 753 The following are additional adverse experiences reported in <1% of patients 754 taking naproxen during clinical trials and through postmarketing reports. 755 Those adverse reactions observed through postmarketing reports are italicized. 756 Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual 757 disorders, pyrexia (chills and fever) 758 Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary 759 edema 760 Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, 761 pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease 762 (ulcerative colitis, Crohn’s disease), nonpeptic gastrointestinal ulceration, 763 ulcerative stomatitis, esophagitis, peptic ulceration 764 Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases 765 have been fatal) 766 Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, 767 agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 768 Metabolic and Nutritional: hyperglycemia, hypoglycemia 769 Nervous System: inability to concentrate, depression, dream abnormalities, 770 insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive 771 dysfunction, convulsions 772 Respiratory: eosinophilic pneumonitis, asthma 773 Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, 774 erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, 775 pustular reaction, systemic lupus erythematoses, bullous reactions, including 776 Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity 777 reactions, including rare cases resembling porphyria cutanea tarda 778 (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or 779 other symptoms suggestive of pseudoporphyria occur, treatment should be 780 discontinued and the patient monitored. 781 Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar 782 optic neuritis, papilledema 783 Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial 784 nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary 785 necrosis, raised serum creatinine 786 Reproduction (female): infertility 787 In patients taking NSAIDs, the following adverse experiences have also been 788 reported in <1% of patients. 789 Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite 790 changes, death 791 Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, 792 hypotension, myocardial infarction 793 Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, 794 glossitis, eructation 795 Hepatobiliary: hepatitis, liver failure 796 Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia 797 Metabolic and Nutritional: weight changes 798 Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, 799 somnolence, tremors, convulsions, coma, hallucinations 800 Respiratory: asthma, respiratory depression, pneumonia 801 Dermatologic: exfoliative dermatitis 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 802 Special Senses: blurred vision, conjunctivitis 803 Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria 804 OVERDOSAGE 805 Symptoms and Signs 806 Significant naproxen overdosage may be characterized by lethargy, dizziness, 807 drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, 808 nausea, transient alterations in liver function, hypoprothrombinemia, renal 809 dysfunction, metabolic acidosis, apnea, disorientation or vomiting. 810 Gastrointestinal bleeding can occur. Hypertension, acute renal failure, 811 respiratory depression, and coma may occur, but are rare. Anaphylactoid 812 reactions have been reported with therapeutic ingestion of NSAIDs, and may 813 occur following an overdose. Because naproxen sodium may be rapidly 814 absorbed, high and early blood levels should be anticipated. A few patients 815 have experienced convulsions, but it is not clear whether or not these were 816 drug-related. It is not known what dose of the drug would be life threatening. 817 The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 818 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. 819 Treatment 820 Patients should be managed by symptomatic and supportive care following a 821 NSAID overdose. There are no specific antidotes. Hemodialysis does not 822 decrease the plasma concentration of naproxen because of the high degree of 823 its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 824 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients 825 seen within 4 hours of ingestion with symptoms or following a large overdose. 826 Forced diuresis, alkalinization of urine or hemoperfusion may not be useful 827 due to high protein binding. 828 DOSAGE AND ADMINISTRATION 829 Carefully consider the potential benefits and risks of NAPROSYN, EC 830 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and 831 other treatment options before deciding to use NAPROSYN, EC 832 NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. 833 Use the lowest effective dose for the shortest duration consistent with 834 individual patient treatment goals (see WARNINGS). 835 After observing the response to initial therapy with NAPROSYN, EC 836 NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the 837 dose and frequency should be adjusted to suit an individual patient’s needs. 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 838 Different dose strengths and formulations (ie, tablets, suspension) of the 839 drug are not necessarily bioequivalent. This difference should be taken 840 into consideration when changing formulation. 841 Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, 842 ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they 843 have pharmacokinetic differences that may affect onset of action. Onset of 844 pain relief can begin within 30 minutes in patients taking naproxen sodium 845 and within 1 hour in patients taking naproxen. Because EC-NAPROSYN 846 dissolves in the small intestine rather than in the stomach, the absorption of 847 the drug is delayed compared to the other naproxen formulations (see 848 CLINICAL PHARMACOLOGY). 849 The recommended strategy for initiating therapy is to choose a formulation 850 and a starting dose likely to be effective for the patient and then adjust the 851 dosage based on observation of benefit and/or adverse events. A lower dose 852 should be considered in patients with renal or hepatic impairment or in elderly 853 patients (see WARNINGS and PRECAUTIONS). 854 Geriatric Patients 855 Studies indicate that although total plasma concentration of naproxen is 856 unchanged, the unbound plasma fraction of naproxen is increased in the 857 elderly. Caution is advised when high doses are required and some adjustment 858 of dosage may be required in elderly patients. As with other drugs used in the 859 elderly, it is prudent to use the lowest effective dose. 860 Patients With Moderate to Severe Renal Impairment 861 Naproxen-containing products are not recommended for use in patients with 862 moderate to severe and severe renal impairment (creatinine clearance <30 863 mL/min) (see WARNINGS: Renal Effects). 864 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 865 To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet 866 should not be broken, crushed or chewed during ingestion. NAPROSYN 867 Suspension should be shaken gently before use. 868 During long-term administration, the dose of naproxen may be adjusted up or 869 down depending on the clinical response of the patient. A lower daily dose 870 may suffice for long-term administration. The morning and evening doses do 871 not have to be equal in size and the administration of the drug more frequently 872 than twice daily is not necessary. 873 In patients who tolerate lower doses well, the dose may be increased to 874 naproxen 1500 mg/day for limited periods of up to 6 months when a higher 875 level of anti-inflammatory/analgesic activity is required. When treating such 876 patients with naproxen 1500 mg/day, the physician should observe sufficient 877 increased clinical benefits to offset the potential increased risk. The morning 878 and evening doses do not have to be equal in size and administration of the 879 drug more frequently than twice daily does not generally make a difference in 880 response (see CLINICAL PHARMACOLOGY). 881 Juvenile Arthritis 882 The use of NAPROSYN Suspension is recommended for juvenile arthritis in 883 children 2 years or older because it allows for more flexible dose titration 884 based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day 885 produced plasma levels of naproxen similar to those seen in adults taking 500 886 mg of naproxen (see CLINICAL PHARMACOLOGY). 887 The recommended total daily dose of naproxen is approximately 10 mg/kg 888 given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup 889 marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the 890 NAPROSYN Suspension. The following table may be used as a guide for 891 dosing of NAPROSYN Suspension: 892 Patient’s Weight Dose Administered as 893 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 894 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 895 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily 896 Management of Pain, Primary Dysmenorrhea, and Acute 897 Tendonitis and Bursitis 898 The recommended starting dose is 550 mg of naproxen sodium as 899 ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg 900 every 6 to 8 hours as required. The initial total daily dose should not exceed 901 1375 mg of naproxen sodium. Thereafter, the total daily dose should not 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 902 exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is 903 more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the 904 management of acute painful conditions when prompt onset of pain relief is 905 desired. NAPROSYN may also be used but EC-NAPROSYN is not 906 recommended for initial treatment of acute pain because absorption of 907 naproxen is delayed compared to other naproxen-containing products (see 908 CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). 909 Acute Gout 910 The recommended starting dose is 750 mg of NAPROSYN followed by 250 911 mg every 8 hours until the attack has subsided. ANAPROX may also be used 912 at a starting dose of 825 mg followed by 275 mg every 8 hours. EC 913 NAPROSYN is not recommended because of the delay in absorption (see 914 CLINICAL PHARMACOLOGY). 915 HOW SUPPLIED 916 NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR 917 LE 250 on one side and scored on the other. Packaged in light-resistant bottles 918 of 100. 919 100’s (bottle): NDC 0004-6313-01. 920 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. 921 Packaged in light-resistant bottles of 100. 922 100’s (bottle): NDC 0004-6314-01. 923 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and 924 scored on the other. Packaged in light-resistant bottles of 100. 925 100’s (bottle): NDC 0004-6316-01. 926 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light 927 resistant containers. 928 NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 929 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 930 0004-0028-28). 931 Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). 932 Dispense in light-resistant containers. Shake gently before use. 933 EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex 934 coated tablets imprinted with NPR EC 375 on one side. Packaged in light 935 resistant bottles of 100. 936 100’s (bottle): NDC 0004-6415-01. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 937 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. 938 Packaged in light-resistant bottles of 100. 939 100’s (bottle): NDC 0004-6416-01. 940 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light 941 resistant containers. 942 ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, 943 engraved with NPS-275 on one side. Packaged in bottles of 100. 944 100’s (bottle): NDC 0004-6202-01. 945 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 946 ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong 947 shaped, engraved with NPS 550 on one side and scored on both sides. 948 Packaged in bottles of 100. 949 100’s (bottle): NDC 0004-6203-01. 950 Store at 15° to 30°C (59° to 86°F) in well-closed containers. 951 Revised: September 2007 952 953 Medication Guide 954 for 955 Non-steroidal Anti-Inflammatory Drugs (NSAIDs) 956 (See the end of this Medication Guide for a list of prescription NSAID 957 medicines.) 958 959 What is the most important information I should know about medicines 960 called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? 961 NSAID medicines may increase the chance of a heart attack or 962 stroke that can lead to death. This chance increases: 963 • with longer use of NSAID medicines 964 • in people who have heart disease 965 966 NSAID medicines should never be used right before or after a 967 heart surgery called a “coronary artery bypass graft (CABG).” 968 NSAID medicines can cause ulcers and bleeding in the stomach 969 and intestines at any time during treatment. Ulcers and bleeding: 970 • can happen without warning symptoms 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 971 • may cause death 972 973 The chance of a person getting an ulcer or bleeding increases 974 with: 975 • taking medicines called “corticosteroids” and 976 “anticoagulants” 977 • longer use 978 • smoking 979 • drinking alcohol 980 • older age 981 • having poor health 982 983 NSAID medicines should only be used: 984 • exactly as prescribed 985 • at the lowest dose possible for your treatment 986 • for the shortest time needed 987 988 What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? 989 NSAID medicines are used to treat pain and redness, swelling, and heat 990 (inflammation) from medical conditions such as: 991 • different types of arthritis 992 • menstrual cramps and other types of short-term pain 993 994 Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? 995 Do not take an NSAID medicine: 996 • if you had an asthma attack, hives, or other allergic reaction with 997 aspirin or any other NSAID medicine 998 • for pain right before or after heart bypass surgery 999 1000 Tell your healthcare provider: 1001 • about all of your medical conditions. 1002 • about all of the medicines you take. NSAIDs and some other 1003 medicines can interact with each other and cause serious side 1004 effects. Keep a list of your medicines to show to your 1005 healthcare provider and pharmacist. 1006 • if you are pregnant. NSAID medicines should not be used by 1007 pregnant women late in their pregnancy. 1008 • if you are breastfeeding. Talk to your doctor. 1009 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 1010 What are the possible side effects of Non-Steroidal Anti-Inflammatory 1011 Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness 1012 1013 Get emergency help right away if you have any of the following 1014 symptoms: • shortness of breath or trouble • slurred speech breathing • swelling of the face or • chest pain throat • weakness in one part or side of your body 1015 1016 Stop your NSAID medicine and call your healthcare provider right away 1017 if you have any of the following symptoms: • nausea • there is blood in your • more tired or weaker than usual bowel movement or it is • itching black and sticky like tar • your skin or eyes look yellow • unusual weight gain • stomach pain • skin rash or blisters with • flu-like symptoms fever • vomit blood • swelling of the arms and legs, hands and feet 1018 1019 These are not all the side effects with NSAID medicines. Talk to your 1020 healthcare provider or pharmacist for more information about NSAID 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 1021 medicines. Call your doctor for medical advice about side effects. You may 1022 report side effects to FDA at 1-800-FDA-1088 or Roche at 1-800-526-6367. 1023 Other information about Non-Steroidal Anti-Inflammatory Drugs 1024 (NSAIDs): 1025 • Aspirin is an NSAID medicine but it does not increase the chance of a 1026 heart attack. Aspirin can cause bleeding in the brain, stomach, and 1027 intestines. Aspirin can also cause ulcers in the stomach and intestines. 1028 • Some of these NSAID medicines are sold in lower doses without a 1029 prescription (over-the-counter). Talk to your healthcare provider before 1030 using over-the-counter NSAIDs for more than 10 days. 1031 1032 NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex® Diclofenac Cataflam®, Voltaren®, Arthrotec™ (combined with misoprostol) Diflunisal Dolobid® Etodolac Lodine®, Lodine®XL Fenoprofen Nalfon®, Nalfon®200 Flurbirofen Ansaid® Ibuprofen Motrin®, Tab-Profen®, Vicoprofen® (combined with hydrocodone), Combunox™ (combined with oxycodone) Indomethacin Indocin®, Indocin®SR, Indo-Lemmon™, Indomethagan™ Ketoprofen Oruvail® Ketorolac Toradol® Mefenamic Acid Ponstel® Meloxicam Mobic® Nabumetone Relafen® Naproxen Naprosyn®, Anaprox®, Anaprox®DS, EC-Naprosyn® , Naprelan®, Naprapac® (copackaged with lansoprazole) Oxaprozin Daypro® Piroxicam Feldene® Sulindac Clinoril® Tolmetin Tolectin®, Tolectin DS®, Tolectin®600 1033 *Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) 1034 NSAID, and is usually used for less than 10 days to treat pain. The OTC 1035 NSAID label warns that long term continuous use may increase the risk of 1036 heart attack or stroke. 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 1037 This Medication Guide has been approved by the U.S. Food and Drug 1038 Administration. 1039 Medication Guide Revised: Month Year 1040 1041 All registered trademarks in this document are the property of their respective 1042 owners. 1043 Distributed by: Logo & Address 1045 1046 1047 XXXXXXXX 1048 Copyright © 1999-200X by Roche Laboratories Inc. All rights reserved. 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:39.613457	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017581s110,18164s60,18965s18,20067s17lbl.pdf', 'application_number': 20067, 'submission_type': 'SUPPL ', 'submission_number': 17}
12,174	(RoChe) EC-NAPROSYN~ (naproxen delayed-release tablets) NAPROSYN~ (naproxen tablets) ANAPROX~/ANAPROX~ DS (naproxen sodium tablets) NAPROSYN~ (naproxen suspension) Rx only Cardiovascular Risk . NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fataL. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). . Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CAB G) surgery (see WARNINGS). Gastrointestinal Risk . NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fataL. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION Naproxen is a proprionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-a- methyl-2-naphthaleneacetic acid and (S)-6-methoxy-a-methyl-2- naphthaJeneacetic acid, sodium salt, respectively. Naproxen and naproxen sodium have the following stiyctures, respectively: ;Oo R..." napro'en (R..COOH) C14HI.o, mol wi 230.26 CH;¡ napro,.n ,odium (R.-COONa) C14H "NaO, mol wl 252.23 CH:iÜ Naproxen has a molecular weight of 230.26 and a molecular formula of C14H1403. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of CI4H13Na03. Naproxen is an odorless, white to off-white crystallne substance. It is lipid- soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coeffcient of naproxen at pH 7.4 is 1.6 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of naproxen, pink tablets containing 375 mg of naproxen and yellow tablets containing 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone and magnesium . stearate. EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric- coated :white tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH4. ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg ofnaproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. The inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Opadry YS-1-4216. NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle containing, sucrose, magnesium aluminum silcate, sorbitol solution and sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C Yellow No.6, imitation pineapple flavor, imitation orange flavor and purified water. The pH ofthe suspension ranges from 2.2 to 3.7. CLINICAL PHARMACOLOGY Pharmacodynamics Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) Pharmacokinetics Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels ofnaproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. Absorption Immediate Release After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN Suspension arc attained in 1 to 4 hours. Delayed Release EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC- NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radio labeled EC-NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (T max) were observed, but there were no differences in total absorption as measured by Cmax and AUC: 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) EC-NAPROSYN* NAPROSYN* 500 mg bid 500 mg bid Cmax (f.g/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61 %) AUCo-12 hr (f.g'hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (T max), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS: Nursing Mothers). Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acyl glucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (":1 %), 6-0-desmethyl naproxen (":1 %) or their conjugates (66% to 92%). The plasma 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPRO~/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate (see WARNINGS: Renal Effects). Special Populations Pediatric Patients In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose ofnaproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not pcrformed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN has not been studied in subjects under the age of 18. Geriatric Patients Studies indicate that although total plasma concentration of nàproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is ..1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Race Pharmacokinetic differences due to race have not been studied. Hepatic Insufficiency Naproxen pharmacokinetics has not been determined in subjects with hepatic insuffciency. Renal Insufficiency Naproxen pharmacokinetics has not been determined in subjects with renal insuffciency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance ..30 mL/min) (see WARNINGS: Renal Effects). CLINICAL STUDIES General Information Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swellng, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadcdness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studics the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (eg, decrease in swellng, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxcn has a "steroid-sparing" effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alonc. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC- NAPROSYN and NAPROSYN showed no significant differences in effcacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long- term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. Geriatric Patients The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. INDICATIONS AND USAGE Carcfully consider the potential benefits and risks of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is indicated: . For the relief of the signs and symptoms of rheumatoid arthritis . For the relief ofthe signs and symptoms of osteoarthritis . For the relief of the signs and symptoms of ankylosing spondylitis . For the relief of the signs and symptoms of juvenile arthritis Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient's weight. Naproxen as NAPROSYN~ ANAPROX, ANAPROX DS and NAPROSYN Suspension is also indicated: . For relief of the signs and symptoms of tendonitis . For relief of the signs and symptoms of bursitis . For relief of the signs and symptoms of acute gout . For the management of pain . For the management of primary dysmenorrhea EC-NAPROSYN is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) CONTRAINDICA TIONS NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated in patients with known hypersensitivity to naproxen and naproxen sodium. NAPROSYN, EC-NAPROSYN,' ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma). NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated for the treatment of peri- operative pain in the setting of coronary artery bypass graft (CAB G) surgery (see WARNINGS). WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fataL. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigatcs the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. (see CONTRAINDICA TIONS). 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) Hypertension NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazid~s or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used with caution in patients with fluid retention, hypertension, or hear failure. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen) of sodium, this should be considered in patients whose overall intakc of sodium must be severely restricted. Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause seflOUS gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fataL. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs OCCU! in approximately 1 % of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID or aspirin potcntiated the risk of bleeding (see PRECAUTIONS - Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to belicve that bleeding at other sites may be similarly potentiated. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated. Renal Effects Long-term administration of NSAIDs has resulted in renal papilary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followcd by recovery to the pretreatment state (see WARNINGS: Advanced Renal Disease). 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Advanced Renal Disease No information is available from controlled clinical studies regarding the use of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension in patients with advanced renal disease. Therefore, treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is not recommended in these patients with advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Skin Reactions NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fataL. These serious events may occur without warning. Patients should be inforied about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus areriosus. PRECAUTIONS General Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE~, and 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspcnsion cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Patients with initial hemoglobin values of 109 or less who are to receive long- term therapy should have hemoglobin values determined periodically. The pharmacological activity of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (AL T) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of AL T or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1 % of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with .symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSY~ (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension should be discontinued. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustmcnt of dosage may be required in these patients. It is prudent to use the lowest effective dose. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet fuction is quantitatively less, of shorter duration, and reversible. Patients receiving either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension who may be adversely affected by alterations in platelct function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fataL. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), N.APROSYN (naproxen suspension) therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, may causc serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when obsei:ving any indicative sign or symptoms. Patients should be apprised ofthe importance of this follow-up (see WARNINGS: Cardiovascular Effects). 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other ;N"SAIDs, can cause GI discomfort and, rarely, serious GI side cffccts, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised ofthe importance of this follow-up (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation). 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, diffculty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek in'mediate emergency help (see WARNINGS). 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. 8. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profie checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspcnsion should be discontinued. Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Antacids and Sucralfate Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Aspirin When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is administered with aspirin, its protein binding is reduced, although the clearance of free NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen and naproxen sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Ch o/es tyramine As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Diuretics Clinical studies, as well as postmarketing observations, have shown that NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the rcnal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory drugs have been rcported to reduce the tubular secretion of methotrexate in an animal modeL. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen with other nonsteroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function. Selective Serotonin Reuptake Inhibitors (SSRls) There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administed concomintantly with SSRIs. Other Information Concerning Drug Interactions Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin- 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) type anticoagulants, sulphonylureas, hydantoins, othcr NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of EC-NAPROSYN is not recommended. Drug/Laboratory Test Interaction Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17- ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy- corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). The maximum dose used was 0.28 times the, systemic exposure to humans at the recommended dose. No evidence oftumorigenicity was found. Pregnancy Teratogenic Effects Pregnancy Category C Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction studies are not always predictive of 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) human response. There are no adequate and well-controlled studies in pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects There is some evidence to suggest that when inhibitors of prostaglandin synthesis are us cd to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (paricularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may advcrsely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension on labor and delivery in pregnant women are unknown. Nursing Mothers The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1 % of maximum naproxen concentration in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided. Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE- AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION), with total 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. Geriatric Use Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric paticnts may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS). Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal fuction, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS: Renal Effects). ADVERSE REACTIONS Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). In controlled clinical trials with about 80 pediatric patients and in well- monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1 % to 10% of patients are: Gastrointestinal (GI) Experiences, including: heartburn , abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache , dizziness * , drowsiness * , lightheadedness, vertigo Dermatologic: pruritus (itching) * , skin eruptions * , ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: edema, palpitations General: dyspnea, thirst Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1 % to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in ..1 % of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chils andfever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease), nonpeptic gastrointestinal ulceration, ulcerative stomatitis, esophagitis, peptic ulceration Hepatobilary: jaundice, abnormal liver function tests, hepatits (some cases have been fatal) Hemic and Lymphatic: eosinophila, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilc pneumonits, asthma Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, . erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitve dermatitis, photosensitvity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragilty, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored Special Senses: hearing impairment, corneal opacity, papilitis, retrobulbar optic neuritis, papiledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papilary necrosis, raised serum creatinine Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in":l % of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulccrs, gastritis, glossitis, eructation syncope, arrhythmia, Hepatobilary: hepatitis, liver failure Hemic and Lymphatic: rectal blecding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Special Senses: blured vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria OVERDOSAGE Symptoms and Signs Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver fuction, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. The oral LDso of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. Treatment Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and other treatment options before dcciding to use NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Use the lowest effectivc dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient's needs, 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation. Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to the other naproxen formulations (see CLINICAL PHARMACOLOGY). The recommended strategy for initiating therapy is to choose a formulation and a staring dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS). Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, . the unbound plasma fraction of naproxen is increased in the eldcrly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest cffective dose. Patients With Moderate to Severe Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance ..30 mL/min) (see WARNINGS: Renal Effects). Rheumatoid Arthritis, Osteoarthritis and Ankylosin9 Spondylitis NAPROSYN 250 mg twice daily or 375 mg twice daily or 500 mg twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN 250 mg (10 mL/2 tsp) twice daily Suspension or 375 mg (15 mL/3 tsp) twice daily or 500 mg (20 mL/4 tsp) twice daily EC-NAPROSYN 375 mg twice daily or 500 mg twice daily 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) . To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. NAPROSYN Suspension should be shaken gently before use. During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffce for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY). Juvenile Arthritis The use of NAPROSYN Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for more flexible dose titration based on the child's weight. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see CLINICAL PHARMACOLOGY). The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 mililiter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing ofNAPROSYN Suspension: Patient's Weight Dose Administered as 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly àbsorbed, ANAPROXIANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). Acute Gout The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting dose of 825 mg followed by 275 mg cvery 8 hours. EC- NAPROSYN is not recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). HOW SUPPLIED NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on one side and scored on the other. Packaged in light-resistant bottles of100. . 100's (bottle): NDC 0004-6313-01. 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-resistant bottles of 100. 100' s (bottle): NDC 0004-6314-01. 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. 100's (bottle): NDC 0004-6316-01. Store at 150 to 30°C (590 to 86°F) in well-closed containers; dispensc in light- resistant containers. NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28). Store at 150 to 30°C (590 to 86°F); avoid excessive heat, above 40°C (104°F). Dispense in light-resistant containers. Shake gently before use. EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. Packaged in light- resistant bottles of 100. 100's (bottle): NDC 0004-6415-01. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) 500 mg: white, oblong coated tablets imprintcd with NPR EC 500 on one side. Packaged in light-resistant bottles of 100. 100' s (bottle): NDC 0004-6416-01. Store at 150 to 30°C (590 to 86°F) in well-closed containers; dispense in light- resistant containers. ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with NPS-275 on one side. Packaged in bottles of 100. 100's (bottle): NDC 0004-6202-01. Store at 15°to 30°C (590 to 86°F) in well-closed containers. ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong.: shaped, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. 100' s (bottle): NDC 0004-6203 -0 1. Store at 150 to 30°C (590 to 86°F) in well-closed containers. Revised: September 2007 Medication Guide for Non-steroidal Anti-Inflammatorv Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: . with longer use of NSAID medicines . in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)." NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: . can happen without warning symptoms 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSY~ (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) . may cause death The chance of a person getting an ulcer or bleeding increases with: . taking medicines called "corticosteroids" and "anticoagulants" . longer use . smoking . drinking alcohol . older age . having poor health NSAID medicines should only be used: . exactly as prescribed . at the lowest dose possible for your treatment . for the shortest time needed ! What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swellng, and heat (inflammation) from medical conditions such as: . different types of arthritis . menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: . if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine . for pain right before or after heart bypass surgery Tell your healthcare provider: . about all of your medical conditions. . about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your health care provider and pharmacist. . if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. . if you are breastfeeding. Talk to your doctor. 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN(j (naproxen suspension) What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: . heart attack . stroke . high blood pressure . heart failure from body swelling (fluid retention) . kidney problems including kidney failure . bleeding and ulcers in the stomach and intestine . low red blood cells (anemia) . life-threatcning skin reactions . life-threatening allergic reactions . liver problems including liver failure . asthma attacks in peoplc who have asthma Other side effects include: . stomach pain . constipation . diarrhea . gas . heartburn . nausea . vomiting . dizziness Get emergency help right away if you have any of the following symptoms: . shortness of breath or trouble breathing . chest pain . weakness in one part or side of your body . slurred speech . swellng of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: . nausea . more tired or weaker than usual . itching . your skin or eyes look yellow . stomach pain . flu-like symptoms . vomit blood . there is blood in your bowel movement or it is black and sticky like tar . unusual weight gain . skin rash or blisters with fever . swellng of the arms and legs, hands and feet These are not all the side effects with NSAID _me.dicines._Talk_ to_your - - healthcare provider or pharmacist for more information about NSAID medicines. 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYNW (naproxen suspension) Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): . Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. . Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcareprovider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradenaiie Celecoxib Celebrex~ Diclofcnac Cataflam~, VoltarenCB, Arthrotec™ (combined with misoprostol) Diflunisal Dolobid~ Etodolac Lodine CB, Lodine CBXL Fenoprofen Nalfon~, Nalfon~200 Flurbirofen Ansaid~ Ibuprofen Motrin~, Tab-Profen~, VicoprofenCB (combined with hydrocodone), Combunox ™ (combined with oxycodone) Indomethacin IndocinCB, Indocin~SR, Indo-Lemmon™, Indomethagan ™ Ketoprofen Oruvail~ Ketorolac Toradol~ Mefenamic Acid Ponstel~ Meloxicam Mobic~ N abumetone Relafen ~ Naproxen NaprosynCB, AnaproxCB, Anaprox~DS, EC-NaprosynCB, Naprelan~, Naprapac~ (copackagcd with lansoprazole) Oxaprozin DayproCB Piroxicam Feldene~ Sulindac ClinorilCB Tolmetin Tolectin~, Tolectin DS~, TolectinCB600 *Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAID, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. Revised: January 2007 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets), NAPROSYN (naproxen suspension) This Medication Guide has been approved by the U.S. Food and Drug Administration. All registered trademarks in this document are the property of their respective owners. Distributed by: (Roche) Pharmaceuticals Roche Laboratories Inc. 340 Kingsland Street Nutley, New Jersey 07110- 1199 xxxxxxxx XXXXXXXX Copyright (9 1999-2001 by Roche Laboratories Inc. All rights reserved. 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:39.825571	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017581s108,18164s58,18965s16,20067s14lbl.pdf', 'application_number': 20067, 'submission_type': 'SUPPL ', 'submission_number': 14}
12,176	EC-NAPROSYN (naproxen delayed-release tablets) NAPROSYN (naproxen tablets) ANAPROX/ANAPROX DS (naproxen sodium tablets) NAPROSYN (naproxen suspension) Rx only Cardiovascular Risk  NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).  Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk  NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). DESCRIPTION Naproxen is a proprionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-- methyl-2-naphthaleneacetic acid and (S)-6-methoxy--methyl-2- naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen sodium have the following structures, respectively: Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C14H13NaO3. Naproxen is an odorless, white to off-white crystalline substance. It is lipid- soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. 1 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of naproxen, pink tablets containing 375 mg of naproxen and yellow tablets containing 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone and magnesium stearate. EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric- coated white tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified water. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4. ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue tablets containing 550 mg of naproxen sodium for oral administration. The inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Opadry YS-1-4216. NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle containing sucrose, magnesium aluminum silicate, sorbitol solution and sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to 3.7. CLINICAL PHARMACOLOGY Pharmacodynamics Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different 2 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) dosage forms of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels. Absorption Immediate Release After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are attained in 1 to 2 hours. The difference in rates between the two products is due to the increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. Delayed Release EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC- NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there were no differences in total absorption as measured by Cmax and AUC: EC-NAPROSYN* 500 mg bid NAPROSYN* 500 mg bid Cmax (µg/mL) 94.9 (18%) 97.4 (13%) Tmax (hours) 4 (39%) 1.9 (61%) AUC0–12 hr (µg·hr/mL) 845 (20%) 767 (15%) Mean value (coefficient of variation) 3 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Antacid Effects When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly. Food Effects When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax). Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS: Nursing Mothers). Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate (see WARNINGS: Renal Effects). 4 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Special Populations Pediatric Patients In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN has not been studied in subjects under the age of 18. Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Race Pharmacokinetic differences due to race have not been studied. Hepatic Insufficiency Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Renal Insufficiency Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects). CLINICAL STUDIES General Information Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute 5 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (eg, decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater 6 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) improvement over that seen with corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These studies indicated that EC- NAPROSYN and NAPROSYN showed no significant differences in efficacy or safety and had similar prevalence of minor GI complaints. Individual patients, however, may find one formulation preferable to the other. Five hundred and fifty-three patients received EC-NAPROSYN during long- term open-label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use. Geriatric Patients The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use 7 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is indicated:  For the relief of the signs and symptoms of rheumatoid arthritis  For the relief of the signs and symptoms of osteoarthritis  For the relief of the signs and symptoms of ankylosing spondylitis  For the relief of the signs and symptoms of juvenile arthritis Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient’s weight. Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is also indicated:  For relief of the signs and symptoms of tendonitis  For relief of the signs and symptoms of bursitis  For relief of the signs and symptoms of acute gout  For the management of pain  For the management of primary dysmenorrhea EC-NAPROSYN is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated in patients with known hypersensitivity to naproxen and naproxen sodium. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma). NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are contraindicated for the treatment of peri- 8 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS: Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used with caution in 9 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) patients with fluid retention, hypertension, or heart failure. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen) of sodium, this should be considered in patients whose overall intake of sodium must be severely restricted. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. 10 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID or aspirin potentiated the risk of bleeding (see PRECAUTIONS: Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see WARNINGS: Advanced Renal Disease). Advanced Renal Disease No information is available from controlled clinical studies regarding the use of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension in patients with advanced renal disease. Therefore, treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is not recommended in these patients with advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close monitoring of the patient’s renal function is advisable and patients should be adequately hydrated. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without 11 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Skin Reactions NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Patients with initial hemoglobin values of 10 g or less who are to receive long- term therapy should have hemoglobin values determined periodically. The pharmacological activity of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions. 12 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension should be discontinued. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. 13 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects). 2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation). 14 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (eg, difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the ductus arteriosus. 8. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be discontinued. Drug Interactions Angiotensin Converting Enzyme (ACE)-inhibitors/Angiotensin Receptor Blockers (ARBs) NSAIDs may diminish the antihypertensive effect of ACE-inhibitors, ARBs, or beta-blockers (including propanolol). Monitor patients taking NSAIDs concomitantly with ACE-inhibitors, ARBs, or beta blockers for changes in blood pressure. 15 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) In addition, in patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised renal function, co-administration of NSAIDs with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. Monitor these patients closely for signs of worsening renal function Antacids and Sucralfate Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Aspirin When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is administered with aspirin, its protein binding is reduced, although the clearance of free NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen and naproxen sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Cholestyramine As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen. Diuretics Clinical studies, as well as postmarketing observations, have shown that NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other 16 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen with other nonsteroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function. Selective Serotonin Reuptake Inhibitors (SSRIs) There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs. Other Information Concerning Drug Interactions Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin- type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of EC-NAPROSYN is not recommended. Drug/Laboratory Test Interaction Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17- ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy- corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. 17 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found. Pregnancy Teratogenic Effects Pregnancy Category C Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension on labor and delivery in pregnant women are unknown. 18 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Nursing Mothers The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided. Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. Geriatric Use Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS). Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS: Renal Effects). ADVERSE REACTIONS Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to 19 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see CLINICAL PHARMACOLOGY). In controlled clinical trials with about 80 pediatric patients and in well- monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal (GI) Experiences, including: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo Dermatologic: pruritus (itching), skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: edema, palpitations General: dyspnea, thirst Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. 20 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease). Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death 21 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria OVERDOSAGE Symptoms and Signs Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs. Treatment Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding. 22 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with NAPROSYN, EC- NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient’s needs. Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation. Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to the other naproxen formulations (see CLINICAL PHARMACOLOGY). The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS). Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Patients With Moderate to Severe Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects). 23 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis NAPROSYN 250 mg or 375 mg or 500 mg twice daily twice daily twice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp) or 375 mg (15 mL/3 tsp) or 500 mg (20 mL/4 tsp) twice daily twice daily twice daily EC-NAPROSYN 375 mg or 500 mg twice daily twice daily To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. NAPROSYN Suspension should be shaken gently before use. During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY). Juvenile Arthritis The use of NAPROSYN Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for more flexible dose titration based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see CLINICAL PHARMACOLOGY). The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing of NAPROSYN Suspension: 24 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Patient’s Weight Dose Administered as 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE). Acute Gout The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC- NAPROSYN is not recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY). HOW SUPPLIED NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on one side and scored on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6313-01. 375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6314-01. 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6316-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light- resistant containers. 25 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28). Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense in light-resistant containers. Shake gently before use. EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex coated tablets imprinted with NPR EC 375 on one side. Packaged in light- resistant bottles of 100. 100’s (bottle): NDC 0004-6415-01. 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. Packaged in light-resistant bottles of 100. 100’s (bottle): NDC 0004-6416-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light- resistant containers. ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with NPS-275 on one side. Packaged in bottles of 100. 100’s (bottle): NDC 0004-6202-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers. ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong- shaped, engraved with NPS 550 on one side and scored on both sides. Packaged in bottles of 100. 100’s (bottle): NDC 0004-6203-01. Store at 15° to 30°C (59° to 86°F) in well-closed containers. Revised: March 2013 26 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Medication Guide for Non-steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:  with longer use of NSAID medicines  in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:  can happen without warning symptoms  may cause death The chance of a person getting an ulcer or bleeding increases with:  taking medicines called “corticosteroids” and “anticoagulants”  longer use  smoking  drinking alcohol  older age  having poor health NSAID medicines should only be used:  exactly as prescribed  at the lowest dose possible for your treatment  for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? 27 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:  different types of arthritis  menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine:  if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine  for pain right before or after heart bypass surgery Tell your healthcare provider:  about all of your medical conditions.  about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.  if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.  if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include:  heart attack  stroke  high blood pressure  heart failure from body swelling (fluid retention)  kidney problems including kidney failure  bleeding and ulcers in the stomach and intestine  low red blood cells (anemia)  life-threatening skin reactions  life-threatening allergic reactions  liver problems including liver failure  asthma attacks in people who have asthma Other side effects include:  stomach pain  constipation  diarrhea  gas  heartburn  nausea  vomiting  dizziness 28 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) Get emergency help right away if you have any of the following symptoms:  shortness of breath or trouble breathing  chest pain  weakness in one part or side of your body  slurred speech  swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:  nausea  more tired or weaker than usual  itching  your skin or eyes look yellow  stomach pain  flu-like symptoms  vomit blood  there is blood in your bowel movement or it is black and sticky like tar  unusual weight gain  skin rash or blisters with fever  swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Genentech at 1-888-835- 2555. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):  Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.  Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. 29 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen ® ® tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, LodineXL Fenoprofen Nalfon, Nalfon200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, IndocinSR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, AnaproxDS, EC-Naprosyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin600 *Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAID, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guide Revised: October 2010 All registered trademarks in this document are the property of their respective owners. 30 Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 31 ENT/NNT/AST/NNS_210516_PIMG_2012_01_K  Year Genentech, Inc. All rights reserved. Reference ID: 3280912 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:39.870295	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017581s111,018164s061,018965s020,020067s018lbl.pdf', 'application_number': 20067, 'submission_type': 'SUPPL ', 'submission_number': 18}
12,177	NDA 20068/S-20 FOSCAVIR ® (foscarnet sodium) INJECTION WARNING RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF FOSCAVIR. FREQUENT MONITORING OF SERUM CREATININE, WITH DOSE ADJUSTMENT FOR CHANGES IN RENAL FUNCTION, AND ADEQUATE HYDRATION WITH ADMINISTRATION OF FOSCAVIR IS IMPERATIVE. (See ADMINISTRATION section; Hydration.) SEIZURES, RELATED TO ALTERATIONS IN PLASMA MINERALS AND ELECTROLYTES, HAVE BEEN ASSOCIATED WITH FOSCAVIR TREATMENT. THEREFORE, PATIENTS MUST BE CAREFULLY MONITORED FOR SUCH CHANGES AND THEIR POTENTIAL SEQUELAE. MINERAL AND ELECTROLYTE SUPPLEMENTATION MAY BE REQUIRED. FOSCAVIR IS INDICATED FOR USE ONLY IN IMMUNOCOMPROMISED PATIENTS WITH CMV RETINITIS AND MUCOCUTANEOUS ACYCLOVIR RESISTANT HSV INFECTIONS. (See INDICATIONS section). DESCRIPTION FOSCAVIR is the brand name for foscarnet sodium. The chemical name of foscarnet sodium is phosphonoformic acid, trisodium salt. Foscarnet sodium is a white, crystalline powder containing 6 equivalents of water of hydration with an empirical formula of Na3 CO5 P•6 H2O and a structural formula FOSCAVIR has the potential to chelate divalent metal ions, such as calcium and magnesium, to form stable coordination compounds. FOSCAVIR INJECTION is a sterile, isotonic aqueous solution for intravenous administration only. The solution is clear and colorless. Each milliliter of FOSCAVIR contains 24 mg of foscarnet sodium hexahydrate in Water for Injection, USP. Hydrochloric acid may have been added to adjust the pH of the solution to 7.4. FOSCAVIR INJECTION contains no preservatives. VIROLOGY Mechanism of Action Foscarnet exerts its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068/S-20 polymerases. Foscarnet does not require activation (phosphorylation) by thymidine kinase or other kinases. Antiviral Activity in Cell Culture The quantitative relationship between the cell culture susceptibility of human cytomegalovirus (CMV) or herpes simplex virus 1 and 2 (HSV-1 and HSV-2) to foscarnet and clinical response to therapy has not been established and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50), vary greatly depending on the assay method used, cell type employed and the laboratory performing the test. A number of sensitive viruses and their EC50 values are listed below (Table 1). The combination antiviral activity of foscarnet and ganciclovir or acyclovir are not antagonistic in cell culture. TABLE 1 Foscarnet Inhibition of Virus Replication in Cell Culture Virus EC50 value (µM) CMV Ganciclovir resistant CMV HSV-1, HSV-2 HSV-TK negative mutant HSV-DNA polymerase mutants 50-800* 190 10-130 67 5-443 Mean = 269 µM Antiviral Activity in vivo Statistically significant decreases in positive CMV cultures from blood and urine have been demonstrated in two studies (FOS-03 and ACTG-015/915) of subjects treated with FOSCAVIR. Although median time to progression of CMV retinitis was increased in subjects treated with FOSCAVIR, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual subjects (Table 2). TABLE 2 Blood and Urine Culture Results from CMV Retinitis Patients Blood +CMV -CMV Baseline End of Induction† 27 1 34 60 Urine +CMV -CMV Baseline End of Induction† 52 21 6 37 A total of 77 subjects were treated with FOSCAVIR in two clinical trials (FOS-03 and ACTG-015/915). Not all subjects had blood or urine cultures done and some subjects had results from both cultures. †(60 mg/kg FOSCAVIR TID for 2–3 weeks). Resistance Cell culture: CMV and HSV isolates with reduced susceptibility to foscarnet have been selected in cell culture by passage of wild type virus in the presence of increasing concentrations of the drug. All foscarnet resistant isolates are known to be generated through amino acid substitutions in the viral DNA polymerase pUL54 (CMV) or pUL30 (HSV) (Table 3). Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 2 TABLE 3 Summary of Foscarnet Resistance-associated DNA Polymerase Amino Acid Substitutions in Cell Culture CMV pUL54 T419M, T552N, S585A, F595I, Q807A, M844T/V, V946L HSV-1 pUL30 Y577H, E597D, A605V, L702H, V714M, L774F, L788M, D780N, L782I, P797T, L802F, V813M, V817M, Y818C, T821M, R842S, S889A, F891C, V892M, D907V, A910V, SRA914-916LCV, V958L, R959H HSV-2 pUL30 _ In vivo: Limited clinical data are available on the development of clinical resistance to foscarnet and many pathways to resistance likely exist. Substitutions documented in the literature in treated patients as associated with foscarnet resistance, are listed in Table 4. TABLE 4 Summary of Foscarnet Resistance-associated Amino Acid Substitutions Observed in Treated Patients CMV pUL54 N495K, Q578H/L, D588E/N, T700A, V715M, E756D/K/Q, L773V, L776M, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, T838A, G841A/S, del 981-982 HSV-1 pUL30 S599L, D672N, R700G V715G, A719T/V, S724N, E798K, G841C/S, A910T, Y941H HSV-2 pUL30 A724T, S725G, S729N, Q732R, L783M, D785N, T844I, L850I, D912V Note: Many additional pathways to foscarnet resistance likely exist The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy. Cross-Resistance: The amino acid substitutions that resulted in reduced susceptibility to foscarnet and either ganciclovir, acyclovir and/or cidofovir are summarized in Tables 5 and 6. TABLE 5 Summary of CMV DNA polymerase Amino Acid Substitutions Conferring Foscarnet Resistance with Cross-Resistance to Ganciclovir and/or Cidofovir Cross-resistant CMV Q578H, D588N, E756K, L773V, L776M, V781I, to pUL54 V787L, L802M, A809V, V812L, T813S, T821I, ganciclovir A834P, G841A/S, Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 3 del 981-982 Cross-resistant to cidofovir CMV pUL54 Q578H, D588N,E756K, L773V, V812L, T813S, A834P, G841A, del 981-982 TABLE 6 Summary of HSV DNA polymerase Amino Acid Substitutions Conferring Foscarnet Resistance with Cross-Resistance to Acyclovir and/or Cidofovir Cross-resistant to acyclovir HSV-1 pUL30 E597D, S599L, A605V, D672N, R700G, L702H, V714M, V715G, A719T/V, S724N, L774F, L778M, D780N, L782I, P797T, E798K, L802F, V813M, V817M, Y818C, T821M, G841C/S, R842S, S889A, F891C/Y, V892M, D907V, A910V/T, SRA914-916LCV, Y941H, V958L, V959H HSV-2 pUL30 A724T, S725G, S729N, Q732R, L783M, D785N, T844I, D912V Marginally cross-resistant to HSV-1 pUL30 V714M, A719V, S724N, L778M, L802F, Y818C, T821M, G841S cidofovir HSV-2 pUL30 L783M CLINICAL PHARMACOLOGY Pharmacokinetics The pharmacokinetics of foscarnet has been determined after administration as an intermittent intravenous infusion during induction therapy in AIDS patients with CMV retinitis. Observed plasma foscarnet concentrations in four studies (FOS-01, ACTG-015, FP48PK, FP49PK) are summarized in Table 7: TABLE 7 Foscarnet Pharmacokinetic Characteristics Parameter 60 mg/kg Q8h 90 mg/kg Q12h C max at steady-state (µM) 589 ± 192 (24) 623 ± 132 (19) C trough at steady-state (µM) 114 ± 91 (24) 63 ± 57 (17) Volume of distribution (L/kg) 0.41 ± 0.13 (12) 0.52 ± 0.20 (18) Plasma half-life (hr) 4.0 ± 2.0 (24) 3.3 ± 1.4 (18) Systemic clearance (L/hr) 6.2 ± 2.1 (24) 7.1 ± 2.7 (18) Renal clearance (L/hr) 5.6 ± 1.9 (5) 6.4 ± 2.5 (13) CSF: plasma ratio 0.69 ± 0.19 (9) † 0.66± 0.11(5) ‡ Values expressed as mean S.D. (number of subjects studied) for each parameter †50 mg/kg Q8h for 28 days, samples taken 3 hrs after end of 1 hr infusion (Astra Report 815-04 AC025-1) ‡90 mg/kg Q12hr for 28 days, samples taken 1hr after end of 2 hr infusion (Hengge et al., 1993) Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 4 Distribution In vitro studies have shown that 14 – 17% of foscarnet is protein bound at plasma drug concentrations of 1 – 1000 μM. The foscarnet terminal half-life determined by urinary excretion was 87.5 ± 41.8 hours, possibly due to release of foscarnet from bone. Postmortem data on several patients in European clinical trials provide evidence that foscarnet does accumulate in bone in humans; however, the extent to which this occurs has not been determined. Special Populations Adults with Impaired Renal Function: The pharmacokinetic properties of foscarnet have been determined in a small group of adult subjects with normal and impaired renal function, as summarized in Table 8: TABLE 8 Pharmacokinetic Parameters (mean ± S.D.) After a Single 60 mg/kg Dose of FOSCAVIR in 4 Groups of Adults with Varying Degrees of Renal Function Parameter Group 1 (N=6) Group 2 (N=6) Group 3 (N=6) Group 4 (N=4) Creatinine clearance (mL/min) 108 ± 16 68 ± 8 34 ± 9 20 ± 4 Foscarnet CL (mL/min/kg) 2.13 ± 0.71 1.33 ± 0.43 0.46 ± 0.14 0.43 ± 0.26 Foscarnet half-life (hr) 1.93 ± 0.12 3.35 ± 0.87 13.0 ± 4.05 25.3 ± 18.7 Group 1 patients had normal renal function defined as a creatinine clearance (CrCl) of >80 mL/min, Group 2 CrCl was 50 – 80 mL/min, Group 3 CrCl was 25 – 49 mL/min and Group 4 CrCl was 10 – 24 mL/min. Total systemic clearance (CL) of foscarnet decreased and half-life increased with diminishing renal function (as expressed by creatinine clearance). Based on these observations, it is necessary to modify the dosage of foscarnet in patients with renal impairment (see DOSAGE AND ADMINISTRATION). Drug Interaction The pharmacokinetics of foscarnet and ganciclovir were not altered in 13 patients receiving either concomitant therapy or daily alternating therapy for maintenance of CMV disease. There is no clinically significant interaction with zidovudine (AZT), or probenecid. CLINICAL TRIALS CMV Retinitis A prospective, randomized, controlled clinical trial (FOS-03) was conducted in 24 patients with AIDS and CMV retinitis comparing treatment with FOSCAVIR to no treatment. Patients received induction treatment of FOSCAVIR, 60 mg/kg every 8 hours for 3 weeks, followed by maintenance treatment with 90 mg/kg/day until retinitis progression (appearance of a new Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 5 lesion or advancement of the border of a posterior lesion greater than 750 microns in diameter). All diagnoses and determinations of retinitis progression were made from masked reading of retinal photographs. The 13 patients randomized to treatment with FOSCAVIR had a significant delay in progression of CMV retinitis compared to untreated controls. Median times to retinitis progression from study entry were 93 days (range 21 – >364) and 22 days (range 7 – 42), respectively. In another prospective clinical trial of CMV retinitis in patients with AIDS (ACTG-915), 33 patients were treated with two to three weeks of FOSCAVIR induction (60 mg/kg TID) and then randomized to either 90 mg/kg/day or 120 mg/kg/day maintenance therapy. The median times from study entry to retinitis progression were not significantly different between the treatment groups, 96 (range 14 – >176) days and 140 (range 16 – >233) days, respectively. In study ACTG 129/FGCRT SOCA study 107 patients with newly diagnosed CMV retinitis were randomized to treatment with FOSCAVIR (induction: 60 mg/kg TID for 2 weeks; maintenance: 90 mg/kg QD) and 127 were randomized to treatment with ganciclovir (induction: 5 mg/kg BID; maintenance: 5 mg/kg QD). The median time to progression on the two drugs was similar (Fos=59 and Gcv=56 days). Relapsed CMV Retinitis The CMV Retinitis Retreatment Trial (ACTG 228/SOCA CRRT) was a randomized, open-label comparison of FOSCAVIR or ganciclovir monotherapy to the combination of both drugs for the treatment of persistently active or relapsed CMV retinitis in patients with AIDS. Subjects were randomized to one of the three treatments: FOSCAVIR 90 mg/kg BID induction followed by 120 mg/kg QD maintenance (Fos); ganciclovir 5 mg/kg BID induction followed by 10 mg/kg QD maintenance (Gcv); or the combination of the two drugs, consisting of continuation of the subject’s current therapy and induction dosing of the other drug (as above), followed by maintenance with FOSCAVIR 90 mg/kg QD plus ganciclovir 5 mg/kg QD (Cmb). Assessment of retinitis progression was performed by masked evaluation of retinal photographs. The median times to retinitis progression or death were 39 days for the FOSCAVIR group, 61 days for the ganciclovir group and 105 days for the combination group. For the alternative endpoint of retinitis progression (censoring on death), the median times were 39 days for the FOSCAVIR group, 61 days for the ganciclovir group and 132 days for the combination group. Due to censoring on death, the latter analysis may overestimate the treatment effect. Treatment modifications due to toxicity were more common in the combination group than in the FOSCAVIR or ganciclovir monotherapy groups (see ADVERSE REACTIONS section). Mucocutaneous Acyclovir Resistant HSV Infections In a controlled trial, patients with AIDS and mucocutaneous, acyclovir-resistant HSV infection were randomized to either FOSCAVIR (N=8) at a dose of 40 mg/kg TID or vidarabine (N=6) at a dose of 15 mg/kg per day. Eleven patients were nonrandomly assigned to receive treatment with FOSCAVIR because of prior intolerance to vidarabine. Lesions in the eight patients randomized to FOSCAVIR healed after 11 to 25 days; seven of the 11 patients nonrandomly treated with FOSCAVIR healed their lesions in 10 to 30 days. Vidarabine was discontinued because of intolerance (N=4) or poor therapeutic response (N=2). In a second trial, forty AIDS Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 6 patients and three bone marrow transplant recipients with mucocutaneous, acyclovir-resistant HSV infections were randomized to receive FOSCAVIR at a dose of either 40 mg/kg BID or 40 mg/kg TID. Fifteen of the 43 patients had healing of their lesions in 11 to 72 days with no difference in response between the two treatment groups. INDICATIONS CMV Retinitis FOSCAVIR is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). Combination therapy with FOSCAVIR and ganciclovir is indicated for patients who have relapsed after monotherapy with either drug. SAFETY AND EFFICACY OF FOSCAVIR HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (e.g., PNEUMONITIS, GASTROENTERITIS); CONGENITAL OR NEONATAL CMV DISEASE; OR NONIMMUNOCOMPROMISED INDIVIDUALS. Mucocutaneous Acyclovir Resistant HSV Infections FOSCAVIR is indicated for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. SAFETY AND EFFICACY OF FOSCAVIR HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER HSV INFECTIONS (e.g., RETINITIS, ENCEPHALITIS); CONGENITAL OR NEONATAL HSV DISEASE; OR HSV IN NONIMMUNOCOMPROMISED INDIVIDUALS. CONTRAINDICATIONS FOSCAVIR is contraindicated in patients with clinically significant hypersensitivity to foscarnet sodium. WARNINGS Renal Impairment THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see ADVERSE REACTIONS section). Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during FOSCAVIR treatment. Renal function should be monitored carefully during both induction and maintenance therapy (see PATIENT MONITORING section). Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of FOSCAVIR. Safety and efficacy data for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour creatinine clearances <50 mL/min are limited. SINCE FOSCAVIR HAS THE POTENTIAL TO CAUSE RENAL IMPAIRMENT, DOSE ADJUSTMENT BASED ON SERUM CREATININE IS NECESSARY. Hydration may reduce the risk of nephrotoxicity. It is recommended that 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of FOSCAVIR to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90-120 mg/kg of FOSCAVIR, and 500 mL with 40–60 mg/kg of FOSCAVIR. Hydration fluid may need to be decreased if clinically warranted. Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 7 After the first dose, the hydration fluid should be administered concurrently with each infusion of FOSCAVIR. Mineral and Electrolyte Abnormalities FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia (see ADVERSE REACTIONS section). FOSCAVIR may also be associated with a dose-related decrease in ionized serum calcium which may not be reflected in total serum calcium. This effect is likely to be related to chelation of divalent metal ions such as calcium by foscarnet. Patients should be advised to report symptoms of low ionized calcium such as perioral tingling, numbness in the extremities and paresthesias. Particular caution and careful management of serum electrolytes is advised in patients with altered calcium or other electrolyte levels before treatment and especially in those with neurologic or cardiac abnormalities and those receiving other drugs known to influence minerals and electrolytes (see PATIENT MONITORING and Drug Interactions sections). Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances. The rate of FOSCAVIR infusion may also affect the decrease in ionized calcium. Therefore, an infusion pump must be used for administration to prevent rapid intravenous infusion (see DOSAGE AND ADMINISTRATION section). Slowing the infusion rate may decrease or prevent symptoms. Seizures Seizures related to mineral and electrolyte abnormalities have been associated with FOSCAVIR treatment (see WARNING section; Mineral and Electrolyte Abnormalities). Several cases of seizures were associated with death. Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions. PRECAUTIONS General Care must be taken to infuse solutions containing FOSCAVIR only into veins with adequate blood flow to permit rapid dilution and distribution to avoid local irritation (see DOSAGE AND ADMINISTRATION). Local irritation and ulcerations of penile epithelium have been reported in male patients receiving FOSCAVIR, possibly related to the presence of drug in the urine. Cases of male and female genital irritation/ulceration have been reported in patients receiving FOSCAVIR. Adequate hydration with close attention to personal hygiene may minimize the occurrence of such events. Due to the sodium content of FOSCAVIR (240 micromoles (5.5 mg) of sodium per mL), avoid FOSCAVIR use when intravenous infusion of a large amount of sodium or water may not be tolerated (e.g. in patients with cardiomyopathy). FOSCAVIR should also be avoided in patients on a controlled sodium diet. Hematopoietic System Anemia has been reported in 33% of patients receiving FOSCAVIR in controlled studies. Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 8 Granulocytopenia has been reported in 17% of patients receiving FOSCAVIR in controlled studies; however, only 1% (2/189) were terminated from these studies because of neutropenia. Information for Patients CMV Retinitis: Patients should be advised that FOSCAVIR is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during or following treatment. They should be advised to have regular ophthalmologic examinations. Mucocutaneous Acyclovir-Resistant HSV Infections: Patients should be advised that FOSCAVIR is not a cure for HSV infections. While complete healing is possible, relapse occurs in most patients. Because relapse may be due to acyclovir-sensitive HSV, sensitivity testing of the viral isolate is advised. In addition, repeated treatment with FOSCAVIR has led to the development of resistance associated with poorer response. In the case of poor therapeutic response, sensitivity testing of the viral isolate also is advised. Effects on Ability to Drive and Use Machines: Adverse effects such as dizziness and convulsions may occur during FOSCAVIR therapy. Patients who experience seizures, dizziness, somnolence or other adverse reactions that could result in impairment, should be advised to avoid driving or operating machinery. General: Patients should be informed that the major toxicities of foscarnet are renal impairment, electrolyte disturbances, and seizures, and that dose modifications and possibly discontinuation may be required. The importance of close monitoring while on therapy must be emphasized. Patients should be advised of the importance of reporting to their physicians symptoms of perioral tingling, numbness in the extremities or paresthesias during or after infusion as possible symptoms of electrolyte abnormalities. Should such symptoms occur, the infusion of FOSCAVIR should be stopped, appropriate laboratory samples for assessment of electrolyte concentrations obtained, and a physician consulted before resuming treatment. The rate of infusion must be no more than 1 mg/kg/minute. The potential for renal impairment may be minimized by accompanying FOSCAVIR administration with hydration adequate to establish and maintain a diuresis during dosing. Drug Interactions A possible drug interaction of FOSCAVIR and intravenous pentamidine has been described. Concomitant treatment of four patients in the United Kingdom with FOSCAVIR and intravenous pentamidine may have caused hypocalcemia; one patient died with severe hypocalcemia. Toxicity associated with concomitant use of aerosolized pentamidine has not been reported. Because FOSCAVIR can reduce serum levels of ionized calcium, extreme caution is advised when used concurrently with other drugs known to influence serum calcium levels (e.g., intravenous pentamidine). Renal impairment and symptomatic hypocalcemia have been observed during concurrent treatment with FOSCAVIR and intravenous pentamidine. Because of foscarnet’s tendency to cause renal impairment, the use of FOSCAVIR should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides, Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 9 amphotericin B, cyclosporine, acyclovir, methotrexate, tacrolimus and intravenous pentamidine (see above) unless the potential benefits outweigh the risks to the patient. When diuretics are indicated, thiazides are recommended over loop diuretics because the latter inhibit renal tubular secretion, and may impair elimination of FOSCAVIR, potentially leading to toxicity. Abnormal renal function has been observed in clinical practice during the use of FOSCAVIR and ritonavir, or FOSCAVIR, ritonavir, and saquinavir. (See DOSAGE and ADMINISTRATION.) Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies were conducted in rats and mice at oral doses of 500 mg/kg/day and 250 mg/kg/day. Oral bioavailability in unfasted rodents is < 20%. No evidence of oncogenicity was reported at plasma drug levels equal to 1/3 and 1/5, respectively, of those in humans (at the maximum recommended human daily dose) as measured by the area-under-the time/concentration curve (AUC). FOSCAVIR showed genotoxic effects in the BALB/3T3 in vitro transformation assay at concentrations greater than 0.5 mcg/mL and an increased frequency of chromosome aberrations in the sister chromatid exchange assay at 1000 mcg/mL. A high dose of foscarnet (350 mg/kg) caused an increase in micronucleated polychromatic erythrocytes in vivo in mice at doses that produced exposures (area under curve) comparable to that anticipated clinically. Pregnancy Pregnancy, Category C: There are no adequate and well-controlled studies of FOSCAVIR in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Animal Data: FOSCAVIR did not adversely affect fertility and general reproductive performance in rats. The results of peri- and post-natal studies in rats were also negative. However, these studies used exposures that are inadequate to define the potential for impairment of fertility at human drug exposure levels. Daily subcutaneous doses up to 75 mg/kg administered to female rats prior to and during mating, during gestation, and 21 days post-partum caused a slight increase (< 5%) in the number of skeletal anomalies compared with the control group. Daily subcutaneous doses up to 75 mg/kg administered to rabbits and 150 mg/kg administered to rats during gestation caused an increase in the frequency of skeletal anomalies/variations. On the basis of estimated drug exposure (as measured by AUC), the 150 mg/kg dose in rats and 75 mg/kg dose in rabbits were approximately one-eighth (rat) and one-third (rabbit) the estimated maximal daily human exposure. These studies are inadequate to define the potential teratogenicity at levels to which women will be exposed. Nursing Mothers Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 10 It is not known whether FOSCAVIR is excreted in human milk; however, in lactating rats administered 75 mg/kg, FOSCAVIR was excreted in maternal milk at concentrations three times higher than peak maternal blood concentrations. Because of the potential for serious adverse events in nursing infants, a decision should be made whether to discontinue nursing or discontinue drug, taking into consideration the importance of the drug to the mother. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Pediatric Use The safety and effectiveness of FOSCAVIR in pediatric patients have not been established. FOSCAVIR is deposited in teeth and bone and deposition is greater in young and growing animals. FOSCAVIR has been demonstrated to adversely affect development of tooth enamel in mice and rats. The effects of this deposition on skeletal development have not been studied. Since deposition in human bone has also been shown to occur, it is likely that it does so to a greater degree in developing bone in pediatric patients. Administration to pediatric patients should be undertaken only after careful evaluation and only if the potential benefits for treatment outweigh the risks. Geriatric Use No studies of the efficacy or safety of FOSCAVIR in persons 65 years of age or older have been conducted. However, FOSCAVIR has been used in patients age 65 years of age and older. The pattern of adverse events seen in these patients is consistent across all age groups. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored. (See DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see WARNINGS section). Approximately 33% of 189 patients with AIDS and CMV retinitis who received FOSCAVIR (60 mg/kg TID), without adequate hydration, developed significant impairment of renal function (serum creatinine ≥ 2.0 mg/dL). The incidence of renal impairment in subsequent clinical trials in which 1000 mL of normal saline or 5% dextrose solution was given with each infusion of FOSCAVIR was 12% (34/280). FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia (15 30%), hypophosphatemia (8–26%) and hyperphosphatemia (6%), hypomagnesemia (15–30%), and hypokalemia (16–48%) (see WARNINGS section). The higher percentages were derived from those patients receiving hydration. FOSCAVIR treatment was associated with seizures in 18/189 (10%) AIDS patients in the initial five controlled studies (see WARNINGS section). Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions predisposing the patient to seizures. The rate of seizures did not increase with Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 11 duration of treatment. Three cases were associated with overdoses of FOSCAVIR (see OVERDOSAGE section). In five controlled U.S. clinical trials the most frequently reported adverse events in patients with AIDS and CMV retinitis are shown in Table 9. These figures were calculated without reference to drug relationship or severity. TABLE 9 Adverse Events Reported in Five Controlled US Clinical Trials n = 189 n = 189 Fever 65% Abnormal Renal Function 27% Nausea 47% Vomiting 26% Anemia 33% Headache 26% Diarrhea 30% Seizures 10% From the same controlled studies, adverse events categorized by investigator as “severe” are shown in Table 10. Although death was specifically attributed to FOSCAVIR in only one case, other complications of FOSCAVIR (i.e., renal impairment, electrolyte abnormalities, and seizures) may have contributed to patient deaths (see WARNINGS section). TABLE 10 Severe Adverse Events n = 189 Death 14% Abnormal Renal Function 14% Marrow Suppression 10% Anemia 9% Seizures 7% From the five initial U.S. controlled trials of FOSCAVIR, the following list of adverse events has been compiled regardless of causal relationship to FOSCAVIR. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medications. Incidence of 5% or Greater Body as a Whole: fever, fatigue, rigors, asthenia, malaise, pain, infection, sepsis, death Central and Peripheral Nervous System: headache, paresthesia, dizziness, involuntary muscle contractions, hypoesthesia, neuropathy, seizures including grand mal seizures (see WARNINGS) Gastrointestinal System: anorexia, nausea, diarrhea, vomiting, abdominal pain Hematologic: anemia, granulocytopenia, leukopenia, neutropenia (see PRECAUTIONS) Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 12 Metabolic and Nutritional: mineral and electrolyte imbalances (see WARNINGS) including hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia Psychiatric. depression, confusion, anxiety Respiratory System: coughing, dyspnea Skin and Appendages: rash, increased sweating Urinary: alterations in renal function including increased serum creatinine, decreased creatinine clearance, and abnormal renal function (see WARNINGS) Special Senses: vision abnormalities Incidence between 1% and 5% Application Site: injection site pain, injection site inflammation Body as a Whole: back pain, chest pain, edema, influenza-like symptoms, bacterial infections, moniliasis, fungal infections, abscess Cardiovascular: hypertension, palpitations, ECG abnormalities including sinus tachycardia, first degree AV block and non-specific ST-T segment changes, hypotension, flushing, cerebrovascular disorder (see WARNINGS) Central and Peripheral Nervous System: tremor, ataxia, dementia, stupor, generalized spasms, sensory disturbances, meningitis, aphasia, abnormal coordination, leg cramps, EEG abnormalities (see WARNINGS) Gastrointestinal: constipation, dysphagia, dyspepsia, rectal hemorrhage, dry mouth, melena, flatulence, ulcerative stomatitis, pancreatitis Hematologic: thrombocytopenia, platelet abnormalities, thrombosis, white blood cell abnormalities, lymphadenopathy Liver and Biliary: abnormal A-G ratio, abnormal hepatic function, increased SGPT, increased SGOT Metabolic and Nutritional: hyponatremia, decreased weight, increased alkaline phosphatase, increased LDH, increased BUN, acidosis, cachexia, thirst, hypocalcemia (see WARNINGS) Musculo-Skeletal: arthralgia, myalgia Neoplasms: lymphoma-like disorder, sarcoma Psychiatric: insomnia, somnolence, nervousness, amnesia, agitation, aggressive reaction, hallucination Respiratory System: pneumonia, sinusitis, pharyngitis, rhinitis, respiratory disorders, respiratory insufficiency, pulmonary infiltration, stridor, pneumothorax, hemoptysis, bronchospasm Skin and Appendages: pruritus, skin ulceration, seborrhea, erythematous rash, maculo papular rash, skin discoloration Special Senses: taste perversions, eye abnormalities, eye pain, conjunctivitis Urinary System: albuminuria, dysuria, polyuria, urethral disorder, urinary retention, urinary tract infections, acute renal failure, nocturia, facial edema Selected adverse events occurring at a rate of less than 1% in the five initial U.S. controlled clinical trials of FOSCAVIR include: syndrome of inappropriate antidiuretic hormone secretion, pancytopenia, hematuria, dehydration, hypoproteinemia, increases in amylase and creatinine phosphokinase, cardiac arrest, coma, and other cardiovascular and neurologic complications. Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 13 Selected adverse event data from the Foscarnet vs. Ganciclovir CMV Retinitis Trial (FGCRT), performed by the Studies of the Ocular Complications of AIDS (SOCA) Research Group, are shown in Table 11 (see CLINICAL TRIALS section). TABLE 11 FGRCT: Selected Adverse Events EVENT GANCICLOVIR FOSCARNET No. of No. of Rates† No. of No. of Rates† Events Patients Events Patients Absolute neutrophil count 63 41 1.30 31 17 0.72 decreasing to <0.50 x 109 per liter Serum creatinine increasing to 6 4 0.12 13 9 0.30 >260 µmol per liter (>2.9 mg/dL) Seizure ‡ 21 13 0.37 19 13 0.37 Catheterization-related infection 49 27 1.26 51 28 1.46 Hospitalization 209 91 4.74 202 75 5.03 * Values for the treatment groups refer only to patients who completed at least one follow-up visit – i.e., 133 to 119 patients in the ganciclovir group and 93 to 100 in the foscarnet group. “Events” denotes all events observed and “patients” the number of patients with one or more of the indicated events. †Per person-year at risk ‡Final frozen SOCA I database dated October 1991 Selected adverse events from ACTG Study 228 (CRRT) comparing combination therapy with FOSCAVIR or ganciclovir monotherapy are shown in Table 12. The most common reason for a treatment change in patients assigned to either FOSCAVIR or ganciclovir was retinitis progression. The most frequent reason for a treatment change in the combination treatment group was toxicity. Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 14 TABLE 12 CRRT: Selected Adverse Events Foscavir Ganciclovir Combination N=88 N=93 N=93 No. No. Rate† No. No. Rate† No. No. Rate† Events Pts.* Events Pts.* Events Pts.* Anemia (Hgb <70g/L) 11 7 0.20 9 7 0.14 19 15 0.33 Neutropenia‡ ANC <0.75 x 109 cells/L 86 32 1.53 95 41 1.51 107 51 1.91 ANC <0.50 x 109 cells/L 50 25 0.91 49 28 0.80 50 28 0.85 Thrombocytopenia Platelets <50 x 109/L 28 14 0.50 19 8 0.43 40 15 0.56 Platelets <20 x 109/L 1 1 0.01 6 2 0.05 7 6 0.18 Nephrotoxicity Creatinine >260 µmol/L 9 7 0.15 10 7 0.17 11 10 0.20 (>2.9 mg/dL) Seizures 6 6 0.17 7 6 0.15 10 5 0.18 Hospitalizations 86 53 1.86 111 59 2.36 118 64 2.36 * Pts. = patients with event; †Rate = events/person/year; ‡ANC = absolute neutrophil count Adverse events that have been reported in post-marketing surveillance include: ventricular arrhythmia, prolongation of QT interval, gamma GT increased, diabetes insipidus (usually nephrogenic), renal calculus, esophageal ulceration, renal tubular acidosis, renal tubular necrosis, crystal-induced nephropathy and muscle disorders including myopathy, myositis, muscle weakness and rare cases of rhabdomyolysis. Cases of vesiculobullous eruptions including erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson Syndrome have been reported. In most cases, patients were taking other medications that have been associated with toxic epidermal necrolysis or Stevens-Johnson Syndrome. OVERDOSAGE In controlled clinical trials performed in the United States, overdosage with FOSCAVIR was reported in 10 out of 189 patients. All 10 patients experienced adverse events and all except one made a complete recovery. One patient died after receiving a total daily dose of 12.5 g for three days instead of the intended 10.9 g. The patient suffered a grand mal seizure and became comatose. Three days later the patient expired with the cause of death listed as respiratory/cardiac arrest. The other nine patients received doses ranging from 1.14 times to 8 times their recommended doses with an average of 4 times their recommended doses. Overall, three patients had seizures, three patients had renal function impairment, four patients had Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 15 paresthesias either in limbs or periorally, and five patients had documented electrolyte disturbances primarily involving calcium and phosphate. Overdose (up to 20 times the recommended dose) has been reported in post-marketing use of FOSCAVIR. Some of these post-marketing reports were relative overdoses in that the dose of FOSCAVIR had not been adjusted in patients with a reduced renal function. The pattern of adverse events associated with a FOSCAVIR overdose is consistent with the known adverse event profile of the drug. There is no specific antidote for FOSCAVIR overdose. Hemodialysis and hydration may be of benefit in reducing drug plasma levels in patients who receive an overdosage of FOSCAVIR, but the effectiveness of these interventions has not been evaluated. The patient should be observed for signs and symptoms of renal impairment and electrolyte imbalance. Medical treatment should be instituted if clinically warranted. DOSAGE AND ADMINISTRATION CAUTION—DO NOT ADMINISTER FOSCAVIR BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF FOSCAVIR MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS. CARE SHOULD BE TAKEN TO AVOID UNINTENTIONAL OVERDOSE BY CAREFULLY CONTROLLING THE RATE OF INFUSION. THEREFORE, AN INFUSION PUMP MUST BE USED. IN SPITE OF THE USE OF AN INFUSION PUMP, OVERDOSES HAVE OCCURRED. ADMINISTRATION Instructions for Administration and Preparation FOSCAVIR is administered by controlled intravenous infusion, either by using a central venous line or by using a peripheral vein. The rate of infusion must be no more than 1 mg/kg/minute. An individualized dose of FOSCAVIR should be calculated on the basis of body weight (mg/kg), renal function, indication of use and dosing frequency (refer to DOSAGE subsection). To reduce the risk of nephrotoxicity, creatinine clearance (mL/min/kg) should be calculated even if serum creatinine is within the normal range, and doses should be adjusted accordingly. An individualized dose at the required concentration (24 mg/mL or 12 mg/mL) for the route of administration (central line or peripheral line) needs to be aseptically prepared prior to dispensing. The standard 24 mg/mL solution may be used with or without dilution when using a central venous catheter for infusion. When a peripheral vein catheter is used, the 24 mg/mL injection must be diluted to a 12 mg/mL concentration with 5% dextrose in water or with a normal saline solution prior to administration to avoid local irritation of peripheral veins. Dilutions and/or removals of excess quantities should be accomplished under aseptic conditions. Solutions thus prepared should be used within 24 hours of first entry into a sealed bottle. Hydration Hydration may reduce the risk of nephrotoxicity. Clinically dehydrated patients should have their condition corrected before initiating FOSCAVIR therapy. It is recommended that 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of FOSCAVIR Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 16 to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90–120 mg/kg of FOSCAVIR, and 500 mL with 40– 60 mg/kg of FOSCAVIR. Hydration fluid may need to be decreased if clinically warranted. Oral rehydration with similar regimens may be considered in certain patients. After the first dose, the hydration fluid should be administered concurrently with each infusion of FOSCAVIR. Compatibility with Other Solutions/Drugs Other drugs and supplements can be administered to a patient receiving FOSCAVIR. However, care must be taken to ensure that FOSCAVIR is only administered with normal saline or 5% dextrose solution and that no other drug or supplement is administered concurrently via the same catheter. Foscarnet has been reported to be chemically incompatible with 30% dextrose, amphotericin B, and solutions containing calcium such as Ringer’s lactate and TPN. Physical incompatibility with other IV drugs has also been reported including acyclovir sodium, ganciclovir, trimetrexate glucuronate, pentamidine isethionate, vancomycin, trimethoprim/sulfamethoxazole, diazepam, midazolam, digoxin, phenytoin, leucovorin, and proclorperazine. Because of foscarnet’s chelating properties, a precipitate can potentially occur when divalent cations are administered concurrently in the same catheter. Parenteral drug products must be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions that are discolored or contain particulate matter should not be used. Accidental Exposure Accidental skin and eye contact with foscarnet sodium solution may cause local irritation and burning sensation. If accidental contact occurs, the exposed area should be flushed with water. DOSAGE THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATES SHOULD NOT BE EXCEEDED. ALL DOSES MUST BE INDIVIDUALIZED FOR PATIENTS’ RENAL FUNCTION. Induction Treatment The recommended initial dose of FOSCAVIR for patients with normal renal function is: • For CMV retinitis patients, either 90 mg/kg (1-1/2 to 2 hour infusion) every twelve hours or 60 mg/kg (minimum one hour infusion) every eight hours over 2-3 weeks depending on clinical response. • For acyclovir-resistant HSV patients, 40 mg/kg (minimum one hour infusion) either every 8 or 12 hours for 2-3 weeks or until healed. An infusion pump must be used to control the rate of infusion. Adequate hydration is recommended to establish a diuresis (see Hydration for recommendation), both prior to and during treatment to minimize renal toxicity (see WARNINGS), provided there are no clinical contraindications. Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 17 Maintenance Treatment Following induction treatment the recommended maintenance dose of FOSCAVIR for CMV retinitis is 90 mg/kg/day to 120 mg/kg/day (individualized for renal function) given as an intravenous infusion over 2 hours. Because the superiority of the 120 mg/kg/day has not been established in controlled trials, and given the likely relationship of higher plasma foscarnet levels to toxicity, it is recommended that most patients be started on maintenance treatment with a dose of 90 mg/kg/day. Escalation to 120 mg/kg/day may be considered should early reinduction be required because of retinitis progression. Some patients who show excellent tolerance to FOSCAVIR may benefit from initiation of maintenance treatment at 120 mg/kg/day earlier in their treatment. An infusion pump must be used to control the rate of infusion with all doses. Again, hydration to establish diuresis both prior to and during treatment is recommended to minimize renal toxicity, provided there are no clinical contraindications (see WARNINGS). Patients who experience progression of retinitis while receiving FOSCAVIR maintenance therapy may be retreated with the induction and maintenance regimens given above or with a combination of FOSCAVIR and ganciclovir (see CLINICAL TRIALS section). Because of physical incompatibility, FOSCAVIR and ganciclovir must NOT be mixed. Use in Patients with Abnormal Renal Function FOSCAVIR should be used with caution in patients with abnormal renal function because reduced plasma clearance of foscarnet will result in elevated plasma levels (see CLINICAL PHARMACOLOGY). In addition, FOSCAVIR has the potential to further impair renal function (see WARNINGS). Safety and efficacy data for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour creatinine clearances < 50 mL/min are limited. Renal function must be monitored carefully at baseline and during induction and maintenance therapy with appropriate dose adjustments for FOSCAVIR as outlined below (see Dose Adjustment and PATIENT MONITORING). During FOSCAVIR therapy if creatinine clearance falls below the limits of the dosing nomograms (0.4 mL/min/kg), FOSCAVIR should be discontinued, the patient hydrated, and monitored daily until resolution of renal impairment is ensured. FOSCAVIR is not recommended in patients undergoing hemodialysis because dosage guidelines have not been established. Dose Adjustment FOSCAVIR dosing must be individualized according to the patient’s renal function status. Refer to Table 13 below for recommended doses and adjust the dose as indicated. Even patients with serum creatinine in the normal range may require dose adjustment; therefore, the dose should be calculated at baseline and frequently thereafter. Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 18 To use this dosing guide, actual 24-hour creatinine clearance (mL/min) must be divided by body weight (kg), or the estimated creatinine clearance in mL/min/kg can be calculated from serum creatinine (mg/dL) using the following formula (modified Cockcroft and Gault equation): For males: 140 – age (x 0.85 for females) = mL/min/kg Serum creatinine x 72 TABLE 13 FOSCAVIR Dosage Guide Induction HSV: Equivalent to CMV: Equivalent to CrCI (mL/min/kg) 80 mg/kg/day total 120 mg/kg/day total (40 mg/kg Q12h) (40 mg/kg Q8h) 180 mg/kg/day total (60 mg/kg Q8h) (90 mg/kg Q12h) >1.4 >1.0 – 1.4 > 0.8 – 1.0 >0.6 – 0.8 >0.5 – 0.6 > 0.4 – 0.5 <0.4 40 Q12h 30 Q12h 20 Q12h 35 Q24h 25 Q24h 20 Q24h Not recommended 40 Q8h 30 Q8h 35 Q12h 25 Q12h 40 Q24h 35 Q24h Not recommended 60 Q8h 90 Q12h 45 Q8h 70 Q12h 50 Q12h 50 Q12h 40 Q12h 80 Q24h 60 Q24h 60 Q24h 50 Q24h 50 Q24h Not recommended Not recommended Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 19 Maintenance CMV: Equivalent to CrCI (mL/min/kg) 90 mg/kg/day (once daily) 120 mg/kg/day (once daily) >1.4 >1.0 – 1.4 >0.8 – 1.0 >0.6 – 0.8 >0.5 – 0.6 >†0.4 – 0.5 <‡0.4 90 Q24h 70 Q24h 50 Q24h 80 Q48h 60 Q48h 50 Q48h Not recommended 120 Q24h 90 Q24h 65 Q24h 105 Q48h 80 Q48h 65 Q48h Not recommended > means “greater than”, †> means “greater than or equal to”, ‡< means “less than” PATIENT MONITORING The majority of patients will experience some decrease in renal function due to FOSCAVIR administration. Therefore it is recommended that creatinine clearance, either measured or estimated using the modified Cockcroft and Gault equation based on serum creatinine, be determined at baseline, 2–3 times per week during induction therapy and once weekly during maintenance therapy, with FOSCAVIR dose adjusted accordingly (see Dose Adjustment). More frequent monitoring may be required for some patients. It is also recommended that a 24-hour creatinine clearance be determined at baseline and periodically thereafter to ensure correct dosing (assuming verification of an adequate collection using creatinine index). FOSCAVIR should be discontinued if creatinine clearance drops below 0.4 mL/min/kg. Due to FOSCAVIR’s propensity to chelate divalent metal ions and alter levels of serum electrolytes, patients must be monitored closely for such changes. It is recommended that a schedule similar to that recommended for serum creatinine (see above) be used to monitor serum calcium, magnesium, potassium and phosphorus. Particular caution is advised in patients with decreased total serum calcium or other electrolyte levels before treatment, as well as in patients with neurologic or cardiac abnormalities, and in patients receiving other drugs known to influence serum calcium levels. Any clinically significant metabolic changes should be corrected. Also, patients who experience mild (e.g., perioral numbness or paresthesias) or severe (e.g., seizures) symptoms of electrolyte abnormalities should have serum electrolyte and mineral levels assessed as close in time to the event as possible. Careful monitoring and appropriate management of electrolytes, calcium, magnesium and creatinine are of particular importance in patients with conditions that may predispose them to seizures (see WARNINGS). Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20068-S/20 Page 20 HOW SUPPLIED FOSCAVIR (foscarnet sodium) INJECTION, 24 mg/mL for intravenous infusion, is supplied in 250 mL glass bottles containing 6000 mg foscarnet sodium (24 mg/mL) as follows: NDC 76310-024-25 250 mL bottles, cases of 10 For Single Use Only. Store between 20° and 25°C (68° and 77°F) [See USP Controlled Room Temperature]. Protect from excessive heat (above 40°C) and from freezing. If refrigerated or exposed to temperatures below the freezing point, precipitation may occur. By keeping the bottle at room temperature with repeated shaking, the precipitate can be brought into solution again. FOSCAVIR INJECTION should be used only if the bottle and seal are intact, a vacuum is present, and the solution is clear and colorless. company logo Manufactured for: Clinigen Healthcare Ltd., DE14 2WW, UK By: Fresenius Kabi Austria GmbH, A-8055 Graz, Austria Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA FOSCAVIR is a trademark of Clinigen Healthcare Ltd. © Clinigen Healthcare Ltd., 2014 Date of revision: November 2014 M087953/01 US Reference ID: 3654928 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:39.973774	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020068s020lbl.pdf', 'application_number': 20068, 'submission_type': 'SUPPL ', 'submission_number': 20}
12,179	NDA 20-073/S-016 Page 3 ROMAZICON® (flumazenil) INJECTION Rx only DESCRIPTION ROMAZICON® (flumazenil) is a benzodiazepine receptor antagonist. Chemically, flumazenil is ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a](1,4) benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculated molecular weight of 303.3, and the following structural formula: Flumazenil is a white to off-white crystalline compound with an octanol:buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions. ROMAZICON is available as a sterile parenteral dosage form for intravenous administration. Each mL contains 0.1 mg of flumazenil compounded with 1.8 mg of methylparaben, 0.2 mg of propylparaben, 0.9% sodium chloride, 0.01% edetate disodium, and 0.01% acetic acid; the pH is adjusted to approximately 4 with hydrochloric acid and/or, if necessary, sodium hydroxide. CLINICAL PHARMACOLOGY Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man. Flumazenil does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids. In animals pretreated with high doses of benzodiazepines over several weeks, ROMAZICON elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects. Pharmacodynamics Intravenous ROMAZICON has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 4 The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil as shown in the following data from a study in normal volunteers. Generally, doses of approximately 0.1 mg to 0.2 mg (corresponding to peak plasma levels of 3 to 6 ng/mL) produce partial antagonism, whereas higher doses of 0.4 to 1 mg (peak plasma levels of 12 to 28 ng/mL) usually produce complete antagonism in patients who have received the usual sedating doses of benzodiazepines. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Eighty percent response will be reached within 3 minutes, with the peak effect occurring at 6 to 10 minutes. The duration and degree of reversal are related to the plasma concentration of the sedating benzodiazepine as well as the dose of ROMAZICON given. In healthy volunteers, ROMAZICON did not alter intraocular pressure when given alone and reversed the decrease in intraocular pressure seen after administration of midazolam. Pharmacokinetics After IV administration, plasma concentrations of flumazenil follow a two-exponential decay model. The pharmacokinetics of flumazenil are dose-proportional up to 100 mg. Distribution Flumazenil is extensively distributed in the extravascular space with an initial distribution half-life of 4 to 11 minutes and a terminal half-life of 40 to 80 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. The volume of distribution at steady-state is 0.9 to 1.1 L/kg. Flumazenil is a weak lipophilic base. Protein binding is approximately 50% and the drug shows no preferential partitioning into red blood cells. Albumin accounts for two thirds of plasma protein binding. Metabolism Flumazenil is completely (99%) metabolized. Very little unchanged flumazenil (<1%) is found in the urine. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate. In preclinical studies there was no evidence of pharmacologic activity exhibited by the de-ethylated free acid. Elimination Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces. Clearance of flumazenil occurs primarily This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 5 by hepatic metabolism and is dependent on hepatic blood flow. In pharmacokinetic studies of normal volunteers, total clearance ranged from 0.8 to 1.0 L/hr/kg. Pharmacokinetic parameters following a 5-minute infusion of a total of 1 mg of ROMAZICON mean (coefficient of variation, range): Cmax (ng/mL) 24 (38%, 11-43) AUC (ng·hr/mL) 15 (22%, 10-22) Vss (L/kg) 1 (24%, 0.8-1.6) Cl (L/hr/kg) 1 (20%, 0.7-1.4) Half-life (min) 54 (21%, 41-79) Food Effects: Ingestion of food during an intravenous infusion of the drug results in a 50% increase in clearance, most likely due to the increased hepatic blood flow that accompanies a meal. Special Populations The Elderly The pharmacokinetics of flumazenil are not significantly altered in the elderly. Gender The pharmacokinetics of flumazenil are not different in male and female subjects. Renal Failure (creatinine clearance <10 mL/min) and Hemodialysis The pharmacokinetics of flumazenil are not significantly affected. Patients With Liver Dysfunction For patients with moderate liver dysfunction, their mean total clearance is decreased to 40% to 60% and in patients with severe liver dysfunction, it is decreased to 25% of normal value, compared with age-matched healthy subjects. This results in a prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Caution should be exercised with initial and/or repeated dosing to patients with liver disease. Drug-Drug Interaction: The pharmacokinetic profile of flumazenil is unaltered in the presence of benzodiazepine agonists and the kinetic profiles of those benzodiazepines studied (ie, diazepam, flunitrazepam, lormetazepam, and midazolam) are unaltered by flumazenil. During the 4-hour steady-state and post infusion of ethanol, there were no pharmacokinetic interactions on ethanol mean plasma levels as compared to placebo when flumazenil doses were given intravenously (at 2.5 hours and 6 hours) nor were interactions of ethanol on the flumazenil elimination half-life found. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 6 Pharmacokinetics in Pediatric Patients The pharmacokinetics of flumazenil have been evaluated in 29 pediatric patients ranging in age from 1 to 17 years who had undergone minor surgical procedures. The average doses administered were 0.53 mg (0.044 mg/kg) in patients aged 1 to 5 years, 0.63 mg (0.020 mg/kg) in patients aged 6 to 12 years, and 0.8 mg (0.014 mg/kg) in patients aged 13 to 17 years. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes). Clearance and volume of distribution, normalized for body weight, were in the same range as those seen in adults, although more variability was seen in the pediatric patients. CLINICAL TRIALS ROMAZICON has been administered in adults to reverse the effects of benzodiazepines in conscious sedation, general anesthesia, and the management of suspected benzodiazepine overdose. Limited information from uncontrolled studies in pediatric patients is available regarding the use of ROMAZICON to reverse the effects of benzodiazepines in conscious sedation only. Conscious Sedation in Adults ROMAZICON was studied in four trials in 970 patients who received an average of 30 mg diazepam or 10 mg midazolam for sedation (with or without a narcotic) in conjunction with both inpatient and outpatient diagnostic or surgical procedures. ROMAZICON was effective in reversing the sedating and psychomotor effects of the benzodiazepine; however, amnesia was less completely and less consistently reversed. In these studies, ROMAZICON was administered as an initial dose of 0.4 mg IV (two doses of 0.2 mg) with additional 0.2 mg doses as needed to achieve complete awakening, up to a maximum total dose of 1 mg. Seventy-eight percent of patients receiving flumazenil responded by becoming completely alert. Of those patients, approximately half responded to doses of 0.4 mg to 0.6 mg, while the other half responded to doses of 0.8 mg to 1 mg. Adverse effects were infrequent in patients who received 1 mg of ROMAZICON or less, although injection site pain, agitation, and anxiety did occur. Reversal of sedation was not associated with any increase in the frequency of inadequate analgesia or increase in narcotic demand in these studies. While most patients remained alert throughout the 3-hour postprocedure observation period, resedation was observed to occur in 3% to 9% of the patients, and was most common in patients who had received high doses of benzodiazepines (see PRECAUTIONS). General Anesthesia in Adults ROMAZICON was studied in four trials in 644 patients who received midazolam as an induction and/or maintenance agent in both balanced and inhalational anesthesia. Midazolam was generally administered in doses ranging from 5 mg to 80 mg, alone and/or in conjunction with muscle relaxants, nitrous oxide, regional or local anesthetics, narcotics and/or inhalational anesthetics. Flumazenil was given as an initial dose of 0.2 mg IV, with additional 0.2 mg doses as needed to reach a complete response, up to a maximum total dose of 1 mg. These doses were effective in reversing sedation and restoring psychomotor function, but did not completely restore memory as tested by picture recall. ROMAZICON was not as effective in the reversal of sedation in patients who had received multiple anesthetic agents in addition to benzodiazepines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 7 Eighty-one percent of patients sedated with midazolam responded to flumazenil by becoming completely alert or just slightly drowsy. Of those patients, 36% responded to doses of 0.4 mg to 0.6 mg, while 64% responded to doses of 0.8 mg to 1 mg. Resedation in patients who responded to ROMAZICON occurred in 10% to 15% of patients studied and was more common with larger doses of midazolam (>20 mg), long procedures (>60 minutes) and use of neuromuscular blocking agents (see PRECAUTIONS). Management of Suspected Benzodiazepine Overdose in Adults ROMAZICON was studied in two trials in 497 patients who were presumed to have taken an overdose of a benzodiazepine, either alone or in combination with a variety of other agents. In these trials, 299 patients were proven to have taken a benzodiazepine as part of the overdose, and 80% of the 148 who received ROMAZICON responded by an improvement in level of consciousness. Of the patients who responded to flumazenil, 75% responded to a total dose of 1 mg to 3 mg. Reversal of sedation was associated with an increased frequency of symptoms of CNS excitation. Of the patients treated with flumazenil, 1% to 3% were treated for agitation or anxiety. Serious side effects were uncommon, but six seizures were observed in 446 patients treated with flumazenil in these studies. Four of these 6 patients had ingested a large dose of cyclic antidepressants, which increased the risk of seizures (see WARNINGS). INDIVIDUALIZATION OF DOSAGE General Principles The serious adverse effects of ROMAZICON are related to the reversal of benzodiazepine effects. Using more than the minimally effective dose of ROMAZICON is tolerated by most patients but may complicate the management of patients who are physically dependent on benzodiazepines or patients who are depending on benzodiazepines for therapeutic effect (such as suppression of seizures in cyclic antidepressant overdose). In high-risk patients, it is important to administer the smallest amount of ROMAZICON that is effective. The 1-minute wait between individual doses in the dose-titration recommended for general clinical populations may be too short for high-risk patients. This is because it takes 6 to 10 minutes for any single dose of flumazenil to reach full effects. Practitioners should slow the rate of administration of ROMAZICON administered to high-risk patients as recommended below. Anesthesia and Conscious Sedation in Adult Patients ROMAZICON is well tolerated at the recommended doses in individuals who have no tolerance to (or dependence on) benzodiazepines. The recommended doses and titration rates in anesthesia and conscious sedation (0.2 mg to 1 mg given at 0.2 mg/min) are well tolerated in patients receiving the drug for reversal of a single benzodiazepine exposure in most clinical settings (see ADVERSE REACTIONS). The major risk will be resedation because the duration of effect of a long-acting (or large dose of a short-acting) benzodiazepine may exceed that of ROMAZICON. Resedation may be treated by giving a repeat dose at no less than 20-minute intervals. For repeat treatment, no more than 1 mg (at 0.2 mg/min doses) should be given at any one time and no more than 3 mg should be given in any one hour. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 8 Benzodiazepine Overdose in Adult Patients The risk of confusion, agitation, emotional lability, and perceptual distortion with the doses recommended in patients with benzodiazepine overdose (3 mg to 5 mg administered as 0.5 mg/min) may be greater than that expected with lower doses and slower administration. The recommended doses represent a compromise between a desirable slow awakening and the need for prompt response and a persistent effect in the overdose situation. If circumstances permit, the physician may elect to use the 0.2 mg/minute titration rate to slowly awaken the patient over 5 to 10 minutes, which may help to reduce signs and symptoms on emergence. ROMAZICON has no effect in cases where benzodiazepines are not responsible for sedation. Once doses of 3 mg to 5 mg have been reached without clinical response, additional ROMAZICON is likely to have no effect. Patients Tolerant to Benzodiazepines ROMAZICON may cause benzodiazepine withdrawal symptoms in individuals who have been taking benzodiazepines long enough to have some degree of tolerance. Patients who had been taking benzodiazepines prior to entry into the ROMAZICON trials, who were given flumazenil in doses over 1 mg, experienced withdrawal-like events 2 to 5 times more frequently than patients who received less than 1 mg. In patients who may have tolerance to benzodiazepines, as indicated by clinical history or by the need for larger than usual doses of benzodiazepines, slower titration rates of 0.1 mg/min and lower total doses may help reduce the frequency of emergent confusion and agitation. In such cases, special care must be taken to monitor the patients for resedation because of the lower doses of ROMAZICON used. Patients Physically Dependent on Benzodiazepines ROMAZICON is known to precipitate withdrawal seizures in patients who are physically dependent on benzodiazepines, even if such dependence was established in a relatively few days of high-dose sedation in Intensive Care Unit (ICU) environments. The risk of either seizures or resedation in such cases is high and patients have experienced seizures before regaining consciousness. ROMAZICON should be used in such settings with extreme caution, since the use of flumazenil in this situation has not been studied and no information as to dose and rate of titration is available. ROMAZICON should be used in such patients only if the potential benefits of using the drug outweigh the risks of precipitated seizures. Physicians are directed to the scientific literature for the most current information in this area. INDICATIONS AND USAGE Adult Patients ROMAZICON is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures, and for the management of benzodiazepine overdose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 9 Pediatric Patients (aged 1 to 17) ROMAZICON is indicated for the reversal of conscious sedation induced with benzodiazepines (see PRECAUTIONS: Pediatric Use). CONTRAINDICATIONS ROMAZICON is contraindicated: • in patients with a known hypersensitivity to flumazenil or benzodiazepines. • in patients who have been given a benzodiazepine for control of a potentially life-threatening condition (eg, control of intracranial pressure or status epilepticus). • in patients who are showing signs of serious cyclic antidepressant overdose (see WARNINGS). WARNINGS THE USE OF ROMAZICON HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF SEIZURES. THESE ARE MOST FREQUENT IN PATIENTS WHO HAVE BEEN ON BENZODIAZEPINES FOR LONG-TERM SEDATION OR IN OVERDOSE CASES WHERE PATIENTS ARE SHOWING SIGNS OF SERIOUS CYCLIC ANTIDEPRESSANT OVERDOSE. PRACTITIONERS SHOULD INDIVIDUALIZE THE DOSAGE OF ROMAZICON AND BE PREPARED TO MANAGE SEIZURES. Risk of Seizures The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations. Possible risk factors for seizures include: concurrent major sedative- hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases, or concurrent cyclic antidepressant poisoning. ROMAZICON is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases ROMAZICON should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with ROMAZICON has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely. Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or barbiturates. Because of the presence of flumazenil, higher than usual doses of benzodiazepines may be required. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 10 Hypoventilation Patients who have received ROMAZICON for the reversal of benzodiazepine effects (after conscious sedation or general anesthesia) should be monitored for resedation, respiratory depression, or other residual benzodiazepine effects for an appropriate period (up to 120 minutes) based on the dose and duration of effect of the benzodiazepine employed. This is because ROMAZICON has not been established in patients as an effective treatment for hypoventilation due to benzodiazepine administration. In healthy male volunteers, ROMAZICON is capable of reversing benzodiazepine-induced depression of the ventilatory responses to hypercapnia and hypoxia after a benzodiazepine alone. However, such depression may recur because the ventilatory effects of typical doses of ROMAZICON (1 mg or less) may wear off before the effects of many benzodiazepines. The effects of ROMAZICON on ventilatory response following sedation with a benzodiazepine in combination with an opioid are inconsistent and have not been adequately studied. The availability of flumazenil does not diminish the need for prompt detection of hypoventilation and the ability to effectively intervene by establishing an airway and assisting ventilation. Overdose cases should always be monitored for resedation until the patients are stable and resedation is unlikely. PRECAUTIONS Return of Sedation ROMAZICON may be expected to improve the alertness of patients recovering from a procedure involving sedation or anesthesia with benzodiazepines, but should not be substituted for an adequate period of postprocedure monitoring. The availability of ROMAZICON does not reduce the risks associated with the use of large doses of benzodiazepines for sedation. Patients should be monitored for resedation, respiratory depression (see WARNINGS) or other persistent or recurrent agonist effects for an adequate period of time after administration of ROMAZICON. Resedation is least likely in cases where ROMAZICON is administered to reverse a low dose of a short-acting benzodiazepine (<10 mg midazolam). It is most likely in cases where a large single or cumulative dose of a benzodiazepine has been given in the course of a long procedure along with neuromuscular blocking agents and multiple anesthetic agents. Profound resedation was observed in 1% to 3% of adult patients in the clinical studies. In clinical situations where resedation must be prevented in adult patients, physicians may wish to repeat the initial dose (up to 1 mg of ROMAZICON given at 0.2 mg/min) at 30 minutes and possibly again at 60 minutes. This dosage schedule, although not studied in clinical trials, was effective in preventing resedation in a pharmacologic study in normal volunteers. The use of ROMAZICON to reverse the effects of benzodiazepines used for conscious sedation has been evaluated in one open-label clinical trial involving 107 pediatric patients between the ages of 1 and 17 years. This study suggested that pediatric patients who have become fully awake following treatment with flumazenil may experience a recurrence of sedation, especially younger patients (ages 1 to 5). Resedation was experienced in 7 of 60 patients who were fully alert 10 minutes after the start of ROMAZICON administration. No patient experienced a return to the baseline level of sedation. Mean time to resedation was 25 minutes (range: 19 to 50 minutes) (see PRECAUTIONS: Pediatric Use). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 11 The safety and effectiveness of repeated flumazenil administration in pediatric patients experiencing resedation have not been established. Use in the ICU ROMAZICON should be used with caution in the ICU because of the increased risk of unrecognized benzodiazepine dependence in such settings. ROMAZICON may produce convulsions in patients physically dependent on benzodiazepines (see INDIVIDUALIZATION OF DOSAGE and WARNINGS). Administration of ROMAZICON to diagnose benzodiazepine-induced sedation in the ICU is not recommended due to the risk of adverse events as described above. In addition, the prognostic significance of a patient’s failure to respond to flumazenil in cases confounded by metabolic disorder, traumatic injury, drugs other than benzodiazepines, or any other reasons not associated with benzodiazepine receptor occupancy is unknown. Use in Benzodiazepine Overdosage ROMAZICON is intended as an adjunct to, not as a substitute for, proper management of airway, assisted breathing, circulatory access and support, internal decontamination by lavage and charcoal, and adequate clinical evaluation. Necessary measures should be instituted to secure airway, ventilation and intravenous access prior to administering flumazenil. Upon arousal, patients may attempt to withdraw endotracheal tubes and/or intravenous lines as the result of confusion and agitation following awakening. Head Injury ROMAZICON should be used with caution in patients with head injury as it may be capable of precipitating convulsions or altering cerebral blood flow in patients receiving benzodiazepines. It should be used only by practitioners prepared to manage such complications should they occur. Use With Neuromuscular Blocking Agents ROMAZICON should not be used until the effects of neuromuscular blockade have been fully reversed. Use in Psychiatric Patients ROMAZICON has been reported to provoke panic attacks in patients with a history of panic disorder. Pain on Injection To minimize the likelihood of pain or inflammation at the injection site, ROMAZICON should be administered through a freely flowing intravenous infusion into a large vein. Local irritation may occur following extravasation into perivascular tissues. Use in Respiratory Disease The primary treatment of patients with serious lung disease who experience serious respiratory depression due to benzodiazepines should be appropriate ventilatory support (see PRECAUTIONS) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 12 rather than the administration of ROMAZICON. Flumazenil is capable of partially reversing benzodiazepine-induced alterations in ventilatory drive in healthy volunteers, but has not been shown to be clinically effective. Use in Cardiovascular Disease ROMAZICON did not increase the work of the heart when used to reverse benzodiazepines in cardiac patients when given at a rate of 0.1 mg/min in total doses of less than 0.5 mg in studies reported in the clinical literature. Flumazenil alone had no significant effects on cardiovascular parameters when administered to patients with stable ischemic heart disease. Use in Liver Disease The clearance of ROMAZICON is reduced to 40% to 60% of normal in patients with mild to moderate hepatic disease and to 25% of normal in patients with severe hepatic dysfunction (see CLINICAL PHARMACOLOGY: Pharmacokinetics). While the dose of flumazenil used for initial reversal of benzodiazepine effects is not affected, repeat doses of the drug in liver disease should be reduced in size or frequency. Use in Drug- and Alcohol-Dependent Patients ROMAZICON should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of benzodiazepine tolerance and dependence observed in these patient populations. ROMAZICON is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes, as such use has not been studied. The administration of flumazenil can precipitate benzodiazepine withdrawal in animals and man. This has been seen in healthy volunteers treated with therapeutic doses of oral lorazepam for up to 2 weeks who exhibited effects such as hot flushes, agitation and tremor when treated with cumulative doses of up to 3 mg doses of flumazenil. Similar adverse experiences suggestive of flumazenil precipitation of benzodiazepine withdrawal have occurred in some adult patients in clinical trials. Such patients had a short-lived syndrome characterized by dizziness, mild confusion, emotional lability, agitation (with signs and symptoms of anxiety), and mild sensory distortions. This response was dose-related, most common at doses above 1 mg, rarely required treatment other than reassurance and was usually short lived. When required, these patients (5 to 10 cases) were successfully treated with usual doses of a barbiturate, a benzodiazepine, or other sedative drug. Practitioners should assume that flumazenil administration may trigger dose-dependent withdrawal syndromes in patients with established physical dependence on benzodiazepines and may complicate the management of withdrawal syndromes for alcohol, barbiturates and cross-tolerant sedatives. Drug Interactions Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied; however, no deleterious interactions were seen when ROMAZICON was administered after narcotics, inhalational anesthetics, muscle relaxants and muscle relaxant antagonists administered in conjunction with sedation or anesthesia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 13 Particular caution is necessary when using ROMAZICON in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially cyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil (see WARNINGS). The use of ROMAZICON is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although ROMAZICON exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients. ROMAZICON blocks the central effects of benzodiazepines by competitive interaction at the receptor level. The effects of nonbenzodiazepine agonists at benzodiazepine receptors, such as zopiclone, triazolopyridazines and others, are also blocked by ROMAZICON. The pharmacokinetics of benzodiazepines are unaltered in the presence of flumazenil and vice versa. There is no pharmacokinetic interaction between ethanol and flumazenil. Use in Ambulatory Patients The effects of ROMAZICON may wear off before a long-acting benzodiazepine is completely cleared from the body. In general, if a patient shows no signs of sedation within 2 hours after a 1-mg dose of flumazenil, serious resedation at a later time is unlikely. An adequate period of observation must be provided for any patient in whom either long-acting benzodiazepines (such as diazepam) or large doses of short-acting benzodiazepines (such as >10 mg of midazolam) have been used (see INDIVIDUALIZATION OF DOSAGE). Because of the increased risk of adverse reactions in patients who have been taking benzodiazepines on a regular basis, it is particularly important that physicians query patients or their guardians carefully about benzodiazepine, alcohol and sedative use as part of the history prior to any procedure in which the use of ROMAZICON is planned (see PRECAUTIONS: Use in Drug- and Alcohol-Dependent Patients). Information for Patients ROMAZICON does not consistently reverse amnesia. Patients cannot be expected to remember information told to them in the postprocedure period and instructions given to patients should be reinforced in writing or given to a responsible family member. Physicians are advised to discuss with patients or their guardians, both before surgery and at discharge, that although the patient may feel alert at the time of discharge, the effects of the benzodiazepine (eg, sedation) may recur. As a result, the patient should be instructed, preferably in writing, that their memory and judgment may be impaired and specifically advised: 1. Not to engage in any activities requiring complete alertness, and not to operate hazardous machinery or a motor vehicle during the first 24 hours after discharge, and it is certain no residual sedative effects of the benzodiazepine remain. 2. Not to take any alcohol or non-prescription drugs during the first 24 hours after flumazenil administration or if the effects of the benzodiazepine persist. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 14 Laboratory Tests No specific laboratory tests are recommended to follow the patient’s response or to identify possible adverse reactions. Drug/Laboratory Test Interactions The possible interaction of flumazenil with commonly used laboratory tests has not been evaluated. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No studies in animals to evaluate the carcinogenic potential of flumazenil have been conducted. Mutagenesis No evidence for mutagenicity was noted in the Ames test using five different tester strains. Assays for mutagenic potential in S. cerevisiae D7 and in Chinese hamster cells were considered to be negative as were blastogenesis assays in vitro in peripheral human lymphocytes and in vivo in a mouse micronucleus assay. Flumazenil caused a slight increase in unscheduled DNA synthesis in rat hepatocyte culture at concentrations which were also cytotoxic; no increase in DNA repair was observed in male mouse germ cells in an in vivo DNA repair assay. Impairment of Fertility A reproduction study in male and female rats did not show any impairment of fertility at oral dosages of 125 mg/kg/day. From the available data on the area under the curve (AUC) in animals and man the dose represented 120x the human exposure from a maximum recommended intravenous dose of 5 mg. Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of the use of flumazenil in pregnant women. Flumazenil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratogenic Effects Flumazenil has been studied for teratogenicity in rats and rabbits following oral treatments of up to 150 mg/kg/day. The treatments during the major organogenesis were on days 6 to 15 of gestation in the rat and days 6 to 18 of gestation in the rabbit. No teratogenic effects were observed in rats or rabbits at 150 mg/kg; the dose, based on the available data on the area under the plasma concentration-time curve (AUC) represented 120x to 600x the human exposure from a maximum recommended intravenous dose of 5 mg in humans. In rabbits, embryocidal effects (as evidenced by increased preimplantation and postimplantation losses) were observed at 50 mg/kg or 200x the human exposure from a maximum recommended intravenous dose of 5 mg. The no-effect dose of 15 mg/kg in rabbits represents 60x the human exposure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 15 Nonteratogenic Effects An animal reproduction study was conducted in rats at oral dosages of 5, 25, and 125 mg/kg/day of flumazenil. Pup survival was decreased during the lactating period, pup liver weight at weaning was increased for the high-dose group (125 mg/kg/day) and incisor eruption and ear opening in the offspring were delayed; the delay in ear opening was associated with a delay in the appearance of the auditory startle response. No treatment-related adverse effects were noted for the other dose groups. Based on the available data from AUC, the effect level (125 mg/kg) represents 120x the human exposure from 5 mg, the maximum recommended intravenous dose in humans. The no-effect level represents 24x the human exposure from an intravenous dose of 5 mg. Labor and Delivery The use of ROMAZICON to reverse the effects of benzodiazepines used during labor and delivery is not recommended because the effects of the drug in the newborn are unknown. Nursing Mothers Caution should be exercised when deciding to administer ROMAZICON to a nursing woman because it is not known whether flumazenil is excreted in human milk. Pediatric Use The safety and effectiveness of ROMAZICON have been established in pediatric patients 1 year of age and older. Use of ROMAZICON in this age group is supported by evidence from adequate and well- controlled studies of ROMAZICON in adults with additional data from uncontrolled pediatric studies including one open-label trial. The use of ROMAZICON to reverse the effects of benzodiazepines used for conscious sedation was evaluated in one uncontrolled clinical trial involving 107 pediatric patients between the ages of 1 and 17 years. At the doses used, ROMAZICON’s safety was established in this population. Patients received up to 5 injections of 0.01 mg/kg flumazenil up to a maximum total dose of 1.0 mg at a rate not exceeding 0.2 mg/min. Of 60 patients who were fully alert at 10 minutes, 7 experienced resedation. Resedation occurred between 19 and 50 minutes after the start of ROMAZICON administration. None of the patients experienced a return to the baseline level of sedation. All 7 patients were between the ages of 1 and 5 years. The types and frequency of adverse events noted in these pediatric patients were similar to those previously documented in clinical trials with ROMAZICON to reverse conscious sedation in adults. No patient experienced a serious adverse event attributable to flumazenil. The safety and efficacy of ROMAZICON in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Pediatric Patients). The safety and efficacy of ROMAZICON have not been established in pediatric patients for reversal of the sedative effects of benzodiazepines used for induction of general anesthesia, for the management of overdose, or for the resuscitation of the newborn, as no well-controlled clinical studies have been performed to determine the risks, benefits and dosages to be used. However, published anecdotal reports discussing the use of ROMAZICON in pediatric patients for these indications have reported similar safety profiles and dosing guidelines to those described for the reversal of conscious sedation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 16 The risks identified in the adult population with ROMAZICON use also apply to pediatric patients. Therefore, consult the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections when using ROMAZICON in pediatric patients. Geriatric Use Of the total number of subjects in clinical studies of flumazenil, 248 were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetics of flumazenil have been studied in the elderly and are not significantly different from younger patients. Several studies of ROMAZICON in subjects over the age of 65 and one study in subjects over the age of 80 suggest that while the doses of benzodiazepine used to induce sedation should be reduced, ordinary doses of ROMAZICON may be used for reversal. ADVERSE REACTIONS Serious Adverse Reactions Deaths have occurred in patients who received ROMAZICON in a variety of clinical settings. The majority of deaths occurred in patients with serious underlying disease or in patients who had ingested large amounts of non-benzodiazepine drugs (usually cyclic antidepressants), as part of an overdose. Serious adverse events have occurred in all clinical settings, and convulsions are the most common serious adverse events reported. ROMAZICON administration has been associated with the onset of convulsions in patients with severe hepatic impairment and in patients who are relying on benzodiazepine effects to control seizures, are physically dependent on benzodiazepines, or who have ingested large doses of other drugs (mixed-drug overdose) (see WARNINGS). Two of the 446 patients who received ROMAZICON in controlled clinical trials for the management of a benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, 1 junctional tachycardia). Adverse Events in Clinical Studies The following adverse reactions were considered to be related to ROMAZICON administration (both alone and for the reversal of benzodiazepine effects) and were reported in studies involving 1875 individuals who received flumazenil in controlled trials. Adverse events most frequently associated with flumazenil alone were limited to dizziness, injection site pain, increased sweating, headache, and abnormal or blurred vision (3% to 9%). Body as a Whole: fatigue (asthenia, malaise), headache, injection site pain, injection site reaction (thrombophlebitis, skin abnormality, rash) Cardiovascular System: cutaneous vasodilation (sweating, flushing, hot flushes) Digestive System: nausea, vomiting (11%) Nervous System: agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation), dizziness (vertigo, ataxia) (10%), emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 17 Special Senses: abnormal vision (visual field defect, diplopia), paresthesia (sensation abnormal, hypoesthesia) All adverse reactions occurred in 1% to 3% of cases unless otherwise marked. *indicates reaction in 3% to 9% of cases. Observed percentage reported if greater than 9%. The following adverse events were observed infrequently (less than 1%) in the clinical studies, but were judged as probably related to ROMAZICON administration and/or reversal of benzodiazepine effects: Nervous System: confusion (difficulty concentrating, delirium), convulsions (see WARNINGS), somnolence (stupor) Special Senses: abnormal hearing (transient hearing impairment, hyperacusis, tinnitus) The following adverse events occurred with frequencies less than 1% in the clinical trials. Their relationship to ROMAZICON administration is unknown, but they are included as alerting information for the physician. Body as a Whole: rigors, shivering Cardiovascular System: arrhythmia (atrial, nodal, ventricular extrasystoles), bradycardia, tachycardia, hypertension, chest pain Digestive System: hiccup Nervous System: speech disorder (dysphonia, thick tongue) Not included in this list is operative site pain that occurred with the same frequency in patients receiving placebo as in patients receiving flumazenil for reversal of sedation following a surgical procedure. Additional Adverse Reactions Reported During Postmarketing Experience The following events have been reported during postapproval use of ROMAZICON. Nervous System: Fear, panic attacks in patients with a history of panic disorders. Withdrawal symptoms may occur following rapid injection of ROMAZICON in patients with long- term exposure to benzodiazepines. DRUG ABUSE AND DEPENDENCE ROMAZICON acts as a benzodiazepine antagonist, blocks the effects of benzodiazepines in animals and man, antagonizes benzodiazepine reinforcement in animal models, produces dysphoria in normal subjects, and has had no reported abuse in foreign marketing. Although ROMAZICON has a benzodiazepine-like structure it does not act as a benzodiazepine agonist in man and is not a controlled substance. OVERDOSAGE There is limited experience of acute overdose with ROMAZICON. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 18 There is no specific antidote for overdose with ROMAZICON. Treatment of an overdose with ROMAZICON should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Intravenous bolus administration of doses ranging from 2.5 to 100 mg (exceeding those recommended) of ROMAZICON, when administered to healthy normal volunteers in the absence of a benzodiazepine agonist, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory test abnormalities. In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects. Reversal with an excessively high dose of ROMAZICON may produce anxiety, agitation, increased muscle tone, hyperesthesia and possibly convulsions. Convulsions have been treated with barbiturates, benzodiazepines and phenytoin, generally with prompt resolution of the seizures (see WARNINGS). DOSAGE AND ADMINISTRATION ROMAZICON is recommended for intravenous use only. It is compatible with 5% dextrose in water, lactated Ringer’s and normal saline solutions. If ROMAZICON is drawn into a syringe or mixed with any of these solutions, it should be discarded after 24 hours. For optimum sterility, ROMAZICON should remain in the vial until just before use. As with all parenteral drug products, ROMAZICON should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. To minimize the likelihood of pain at the injection site, ROMAZICON should be administered through a freely running intravenous infusion into a large vein. Reversal of Conscious Sedation Adult Patients For the reversal of the sedative effects of benzodiazepines administered for conscious sedation, the recommended initial dose of ROMAZICON is 0.2 mg (2 mL) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a second dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL). The dosage should be individualized based on the patient’s response, with most patients responding to doses of 0.6 mg to 1 mg (see INDIVIDUALIZATION OF DOSAGE). In the event of resedation, repeated doses may be administered at 20-minute intervals as needed. For repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour. It is recommended that ROMAZICON be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see INDIVIDUALIZATION OF DOSAGE). Pediatric Patients For the reversal of the sedative effects of benzodiazepines administered for conscious sedation in pediatric patients greater than 1 year of age, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 19 waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) can be administered and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower. The dose should be individualized based on the patient’s response. The mean total dose administered in the pediatric clinical trial of flumazenil was 0.65 mg (range: 0.08 mg to 1.00 mg). Approximately one-half of patients required the maximum of five injections. Resedation occurred in 7 of 60 pediatric patients who were fully alert 10 minutes after the start of ROMAZICON administration (see PRECAUTIONS: Pediatric Use). The safety and efficacy of repeated flumazenil administration in pediatric patients experiencing resedation have not been established. It is recommended that ROMAZICON be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see INDIVIDUALIZATION OF DOSAGE). The safety and efficacy of ROMAZICON in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established. Reversal of General Anesthesia in Adult Patients For the reversal of the sedative effects of benzodiazepines administered for general anesthesia, the recommended initial dose of ROMAZICON is 0.2 mg (2 mL) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL). The dosage should be individualized based on the patient’s response, with most patients responding to doses of 0.6 mg to 1 mg (see INDIVIDUALIZATION OF DOSAGE). In the event of resedation, repeated doses may be administered at 20-minute intervals as needed. For repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour. It is recommended that ROMAZICON be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see INDIVIDUALIZATION OF DOSAGE). Management of Suspected Benzodiazepine Overdose in Adult Patients For initial management of a known or suspected benzodiazepine overdose, the recommended initial dose of ROMAZICON is 0.2 mg (2 mL) administered intravenously over 30 seconds. If the desired level of consciousness is not obtained after waiting 30 seconds, a further dose of 0.3 mg (3 mL) can be administered over another 30 seconds. Further doses of 0.5 mg (5 mL) can be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg. Do not rush the administration of ROMAZICON. Patients should have a secure airway and intravenous access before administration of the drug and be awakened gradually (see PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-073/S-016 Page 20 Most patients with a benzodiazepine overdose will respond to a cumulative dose of 1 mg to 3 mg of ROMAZICON, and doses beyond 3 mg do not reliably produce additional effects. On rare occasions, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg (administered slowly in the same manner). If a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg of ROMAZICON, the major cause of sedation is likely not to be due to benzodiazepines, and additional ROMAZICON is likely to have no effect. In the event of resedation, repeated doses may be given at 20-minute intervals if needed. For repeat treatment, no more than 1 mg (given as 0.5 mg/min) should be given at any one time and no more than 3 mg should be given in any one hour. Safety and Handling ROMAZICON is supplied in sealed dosage forms and poses no known risk to the healthcare provider. Routine care should be taken to avoid aerosol generation when preparing syringes for injection, and spilled medication should be rinsed from the skin with cool water. HOW SUPPLIED 5 mL multiple-use vials containing 0.1 mg/mL flumazenil — boxes of 10 (NDC 0004-6911-06); 10 mL multiple-use vials containing 0.1 mg/mL flumazenil — boxes of 10 (NDC 0004-6912-06). Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Distributed by: 10082938Revised: February 2007 Copyright © 1998-2007 by Roche Laboratories Inc. All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:40.153835	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020073s016lbl.pdf', 'application_number': 20073, 'submission_type': 'SUPPL ', 'submission_number': 16}
12,178	1 Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. DESCRIPTION Desogen® (desogestrel and ethinyl estradiol) Tablets provide an oral contraceptive regimen of 21 white round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4- en-20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol). Inactive ingredients include vitamin E, corn starch, povidone, stearic acid, colloidal silicon dioxide, lactose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and talc. Desogen® also contains 7 green round tablets containing the following inert ingredients: lactose, corn starch, magnesium stearate, FD&C Blue No. 2 aluminum lake, ferric oxide, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and talc. The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.41, respectively. The structural formulas are as follows: C22H30O C20H24O2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 CLINICAL PHARMACOLOGY Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). Receptor-binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91,92). The relevance of this latter finding in humans is unknown. Pharmacokinetics Absorption Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of etonogestrel, is approximately 84%. In the third cycle of use after a single dose of Desogen® (desogestrel and ethinyl estradiol) Tablets, maximum concentrations of etonogestrel of 2805±1203 pg/mL (mean±SD) are reached at 1.4±0.8 hours. The area under the curve (AUC0–∞) is 33,858±11,043 pg/mL•hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5840±1667 pg/mL are reached at 1.4±0.9 hours. The minimum plasma levels of etonogestrel at steady state are 1400±560 pg/mL. The AUC0–24 at steady state is 52,299±17,878 pg/mL•hr. The mean AUC0–∞ for etonogestrel at single dose is significantly lower than the mean AUC0–24 at steady state. This indicates that the kinetics of etonogestrel are non-linear due to an increase in binding of etonogestrel to SHBG in the cycle, attributed to increased SHBG levels which are induced by the daily administration of ethinyl estradiol. SHBG levels increased significantly in the third treatment cycle from day 1 (150±64 nmol/L) to day 21 (230±59 nmol/L). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of Desogen®, the relative bioavailability is approximately 83%. In the third cycle of use after a single dose of Desogen®, maximum concentrations of ethinyl estradiol of 95±34 pg/mL are reached at 1.5±0.8 hours. The AUC0–∞ is 1471±268 pg/mL•hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141±48 pg/mL are reached at about 1.4±0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24±8.3 pg/mL. The AUC0–24, at steady state is 1117±302 pg/mL•hr. The mean AUC0–∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0–24 at steady state. This finding indicates linear kinetics for ethinyl estradiol. Distribution Etonogestrel, the active metabolite of desogestrel, was found to be 98% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is primarily bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96–99). Metabolism Desogestrel: Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. In vitro data suggest an important role for the cytochrome P450 CYP2C9 in the bioactivation of desogestrel. Further metabolism of etonogestrel into 6β-hydroxy, etonogestrel and 6β-13ethyl-dihydroxylated metabolites as major metabolites is catalyzed by CYP3A4. Other metabolites (i.e., 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel) also have been identified and these metabolites may undergo glucuronide and sulfate conjugation. Ethinyl estradiol: Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol, escaping gut wall conjugation, undergoes phase I metabolism and hepatic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy- ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation. Excretion Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. The elimination half- life of etonogestrel is approximately 38±20 hours at steady state. The elimination half-life of ethinyl estradiol is 26±6.8 hours at steady state. Special Populations Race There is no information to determine the effect of race on the pharmacokinetics of Desogen® (desogestrel and ethinyl estradiol) Tablets. Hepatic Insufficiency No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Desogen®. However, steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS). Renal Insufficiency No formal studies were conducted to evaluate the effect of renal disease on the disposition of Desogen®. Drug –Drug Interactions Interactions between desogestrel/ethinly estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with Desogen® (see PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 INDICATIONS AND USAGE Desogen® (desogestrel and ethinyl estradiol) Tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptives are highly effective. Table 1 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 TABLE 1 PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR: UNITED STATES. % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year3 Method Typical Use1 Perfect Use2 (1) (2) (3) (4) Chance4 85 85 Spermicides5 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal6 2 Post-Ovulation 1 Withdrawal 19 4 Cap7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Diaphragm7 20 6 56 Condom8 Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T 380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera 0.3 0.3 70 Norplant and Norplant-2 0.05 0.05 88 Female sterilization 0.5 0.5 100 Male sterilization 0.15 0.10 100 Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces risk of pregnancy by at least 75%9 Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10 Source: Trussell J, Stewart F, Contraceptive Efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998. 1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason 3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year 4 The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% became pregnant in one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandon contraception altogether 5 Foams, creams, gels, vaginal suppositories and vaginal film 6 Cervical mucous (ovulation) method supplemented by calendar in the preovulatory and basal body temperature in the postovulatory phases 7 With spermicidal cream or jelly 8 Without spermicides 9 The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills) 10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced or the baby reaches six months of age This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 CONTRAINDICATIONS Oral contraceptives should not be used in women who currently have the following conditions: • Thrombophlebitis or thromboembolic disorders • A past history of deep vein thrombophlebitis or thromboembolic disorders • Cerebral vascular or coronary artery disease (current or history) • Valvular heart disease with thrombogenic complications • Severe hypertension • Diabetes with vascular involvement • Headaches with focal neurological symptoms • Major surgery with prolonged immobilization • Known or suspected carcinoma of the breast (or personal history of breast cancer) • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia • Undiagnosed abnormal genital bleeding • Cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use • Hepatic tumors (benign or malignant) or active liver disease • Known or suspected pregnancy • Heavy smoking (≥15 cigarettes per day) and over age 35 • Hypersensitivity to any of the components of Desogen® WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited thrombophilias, hypertension, hyperlipidemias, obesity, and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among non- users. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and non-users. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the authors’ permission). For further information, the reader is referred to a text on epidemiologic methods. 1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS a. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease (2,3,19–24). Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization (25). The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped (2). Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives (100–102). In general, these studies indicate an approximate two-fold increased risk, which corresponds to an additional 1–2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this two-fold increase in risk. A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives (9,26). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (9,26). If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breast-feed. b. Myocardial infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (4–10). The risk is very low in women under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases (11). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non- smokers over the age of 40 (Table 2) among women who use oral contraceptives. TABLE 2: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS, AND ORAL CONTRACEPTIVE USE. EVER-USERS EVER-USERS CONTROLS CONTROLS AGE NON-SMOKERS SMOKERS NON-SMOKERS SMOKERS 15–24 0.0 10.5 0.0 0.0 25–34 4.4 14.2 2.7 4.2 35–44 21.5 63.4 6.4 15.2 45+ 52.4 206.7 11.4 27.9 Adapted from P.M. Layde and V. Beral, ref. #12. Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity (13). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (14–18). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 c. Cerebrovascular diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and non-users, for both types of strokes, while smoking interacted to increase the risk of hemorrhagic stroke (27–29). In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension (30). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension (30). The attributable risk is also greater in older women (3). Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke. d. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (31–33). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (14–16). A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on a product containing the lowest hormone content that is judged appropriate for the individual. e. Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups (8). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small (34). However, both studies were performed with oral contraceptive formulations containing 0.05 mg or higher of estrogens. 2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 3). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s – but not reported until 1983 (35). However, current clinical practice involves the use of lower estrogen formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling. Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (103,104), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. Therefore, the Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective and meets the individual patient needs. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 TABLE 3: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15–19 20–24 25–29 30–34 35–39 40–44 No fertility control methods* 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 non-smoker Oral contraceptives 2.2 3.4 6.6 13.5 51.1 117.2 smoker IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth related ** Deaths are method related Adapted from H.W. Ory, ref. #35. 3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS Numerous epidemiologic studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. Although the risk of breast cancer may be slightly increased among current users of oral contraceptives (RR = 1.24), this excess risk decreases over time after oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use, and no relationships have This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less advanced clinically than in never-users. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor. Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women (45-48). However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. 4. HEPATIC NEOPLASIA Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose (49). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (50,51). Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (52–54) in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the US and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 5. OCULAR LESIONS There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (55–57). Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned (55,56,58,59), when oral contraceptives are taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 7. GALLBLADDER DISEASE Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (60,61). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (62– 64). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users (17). Oral contraceptives containing greater than 75 micrograms of estrogen cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (65). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (17,66). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (67). Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 9. ELEVATED BLOOD PRESSURE Women with severe hypertension should not be started on hormonal contraceptives. An increase in blood pressure has been reported in women taking oral contraceptives (68) and this increase is more likely in older oral contraceptive users (69) and with continued use (61). Data from the Royal College of General Practitioners (12) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases, or renal disease (70) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (69), and there is no difference in the occurrence of hypertension between ever- and never-users (68,70,71). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 10. HEADACHE The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. 11. BLEEDING IRREGULARITIES Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. If bleeding persists or recurs, non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent. 12. ECTOPIC PREGNANCY Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. PRECAUTIONS 1. SEXUALLY TRANSMITTED DISEASES Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 2. PHYSICAL EXAMINATION AND FOLLOW UP It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. LIPID DISORDERS Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis. 4. LIVER FUNCTION If jaundice develops in any woman receiving oral contraceptives, the medication should be discontinued. The hormones in Desogen® may be poorly metabolized in patients with impaired liver function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 5. FLUID RETENTION Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. EMOTIONAL DISORDERS Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 7. CONTACT LENSES Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8. DRUG INTERACTIONS Changes in contraceptive effectiveness associated with co-administration of other drugs: a. Anti-infective agents and anticonvulsants Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with some antibiotics, anticonvulsants, and other drugs that increase metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include barbiturates, rifampin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate and griseofulvin. Since desogestrel is mainly metabolized by the cytochrome P450 2C9 enzyme (CYP 2C9) to form etonogestrel, the active progestin, there is a possibility of interaction with CYP 2C9 substrates or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 inhibitors (such as: ibuprofen, piroxicam, naproxen, phenytoin, fluconazole, diclofenac, tolbutamide, glipizide, celecoxib, sulfamethoxazole, isoniazid, torsemide, irbesartan, losartan, and valsartan). The clinical relevance of these interactions is unknown. b. Anti-HIV protease inhibitors Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The efficacy and safety of these oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Health care providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. c. Herbal products Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. Increase in plasma hormone levels associated with co-administered drugs: Co-administration of atorvastatin and certain ethinyl estradiol containing oral contraceptives increased AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Changes in plasma levels of co-administered drugs: Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, have been noted when these drugs were administered with oral contraceptives. No formal drug-drug interaction studies were conducted with Desogen®. 9. INTERACTIONS WITH LABORATORY TESTS Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 10. CARCINOGENESIS See WARNINGS section. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 11. PREGNANCY Pregnancy Category X (see CONTRAINDICATIONS and WARNINGS sections). 12. NURSING MOTHERS Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. 13. PEDIATRIC USE Safety and efficacy of Desogen® (desogestrel and ethinyl estradiol) Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 14. GERIATRIC USE This product has not been studied in women over 65 years of age and is not indicated in this population. INFORMATION FOR THE PATIENT See Patient Labeling Printed Below This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section): • Thrombophlebitis and venous • Cerebral hemorrhage thrombosis with or without embolism • Cerebral thrombosis • Arterial thromboembolism • Hypertension • Pulmonary embolism • Gallbladder disease • Myocardial infarction • Hepatic adenomas or benign liver tumors There is evidence of an association between the following conditions and the use of oral contraceptives: • Mesenteric thrombosis • Retinal thrombosis The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: • Nausea • Change in weight or appetite (increase or decrease) • Vomiting • Change in cervical ectropion and secretion • Gastrointestinal symptoms (such as • Possible diminution in lactation when given abdominal pain, cramps and bloating) immediately postpartum • Breakthrough bleeding • Cholestatic jaundice • Spotting • Migraine headache • Change in menstrual flow • Rash (allergic) • Amenorrhea • Mood changes, including depression • Temporary infertility after • Vaginitis, including candidiasis discontinuation of treatment • Change in corneal curvature (steepening) • Edema/fluid retention • Intolerance to contact lenses This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 • Melasma/chloasma which may persist • Exacerbation of systemic lupus erythematosus • Breast changes: tenderness, pain, • Exacerbation of chorea enlargement, and secretion • Anaphylactic/anaphylactoid reactions, including • Decrease in serum folate levels urticaria, angioedema, and severe reactions with • Exacerbation of porphyria respiratory and circulatory symptoms • Aggravation of varicose veins The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted: • Pre-menstrual syndrome • Erythema nodosum • Cataracts • Hemorrhagic eruption • Cystitis-like syndrome • Impaired renal function • Headache • Hemolytic uremic syndrome • Nervousness • Acne • Dizziness • Changes in libido • Hirsutism • Colitis • Loss of scalp hair • Budd-Chiari Syndrome • Erythema multiforme • Optic neuritis, which may lead to partial or complete • Dysmenorrhea loss of vision • Pancreatitis OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiologic studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (73–78). Effects on menses: • increased menstrual cycle regularity • decreased blood loss and decreased incidence of iron deficiency anemia • decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: • decreased incidence of functional ovarian cysts • decreased incidence of ectopic pregnancies Effects from long-term use: • decreased incidence of fibroadenomas and fibrocystic disease of the breast • decreased incidence of acute pelvic inflammatory disease • decreased incidence of endometrial cancer • decreased incidence of ovarian cancer DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, Desogen® (desogestrel and ethinyl estradiol) Tablets must be taken exactly as directed, at the same time every day, and at intervals not exceeding 24 hours. Desogen® may be initiated using either a Sunday start or a Day 1 start. Note: Each cycle pack dispenser is preprinted with the days of the week, starting with Sunday, to facilitate a Sunday start regimen. Six different “day label strips” are provided with each cycle pack This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 dispenser in order to accommodate a Day 1 start regimen. In this case, the patient should place the self- adhesive “day label strip” that corresponds to her starting day over the preprinted days. DURING THE FIRST CYCLE OF USE: IMPORTANT: The possibility of ovulation and conception prior to initiation of use of Desogen® should be considered. A woman can begin to take Desogen® either on the first Sunday after the onset of her menstrual period (Sunday Start) or on the first day of her menstrual period (Day 1 Start). When switching from another oral contraceptive, Desogen® should be started on the same day that a new pack of the previous oral contraceptive would have been started. SUNDAY START When initiating a Sunday start regimen, another method of contraception, such as condoms or spermicide, should be used for the first 7 consecutive days of taking Desogen®. Using a Sunday start, tablets are taken daily without interruption as follows: The first white tablet should be taken on the first Sunday after menstruation begins (if menstruation begins on Sunday, the first white tablet is taken on that day). Tablets are then taken sequentially following the arrows marked on the dispenser. One white tablet is taken daily for 21 days, followed by 1 green (inactive) tablet daily for 7 days. For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day (Sunday) after taking the last green tablet. [If switching from a different Sunday Start oral contraceptive, the first Desogen® (desogestrel and ethinyl estradiol) tablet should be taken on the same day that a new pack of the previous oral contraceptive would have been started.] If a patient misses 1 white (active) tablet in Weeks 1, 2, or 3, she should take the missed tablet as soon as she remembers. If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. The patient should be instructed to use a back-up This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 method of birth control (such as condoms or spermicide) if she has intercourse in the 7 days after she restarts her pills. If the patient misses 2 consecutive white tablets in the third week or misses 3 or more white tablets in a row at any time during the cycle, the patient should keep taking 1 white tablet daily until the next Sunday. On Sunday the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after restarting her pills. Complete instructions to facilitate patient counseling on proper pill usage can be found in Detailed or Brief Patient Labeling ("How to take the Pill" section). DAY 1 START Counting the first day of menstruation as “Day 1”, the first white tablet should be taken on the first day of menstrual bleeding. Tablets are then taken sequentially without interruption as follows: One white tablet daily for 21 days, then one green (inactive) tablet daily for 7 days. For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day after taking the last green tablet. If switching directly from another oral contraceptive, the first white tablet should be taken on the same day that a new pack of the previous oral contraceptive would have been started. If a patient misses 1 white tablet, she should take the missed tablet as soon as she remembers. If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. The patient should be instructed to use a back-up method of birth control (such as condoms or spermicide) if she has intercourse in the 7 days after she restarts her pills. If the patient misses 2 consecutive white tablets in the third week or misses 3 or more white tablets in a row at any time during the cycle, the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after she restarts her pills. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 Complete instructions to facilitate patient counseling on proper pill usage can be found in Detailed or Brief Patient Labeling ("How to Take the Pill" section). ADDITIONAL INSTRUCTIONS FOR BOTH SUNDAY AND DAY 1 STARTS If Spotting or Breakthrough Bleeding Occurs Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, non- functional causes should be considered. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If both pregnancy and pathology have been excluded, time or a change to another preparation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease. Use of Desogen® in the Event of a Missed Menstrual Period 1. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and Desogen® use should be discontinued if pregnancy is confirmed. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Desogen® should be discontinued if pregnancy is confirmed. Use of Desogen® Postpartum The use of Desogen® for contraception may be initiated 4 to 6 weeks postpartum in women who elect not to breast feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS for “Nursing Mothers”). If the patient starts on Desogen® postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a white tablet has been taken daily for 7 consecutive days. HOW SUPPLIED Desogen® (desogestrel and ethinyl estradiol) Tablets contain 21 round white tablets and 7 round green tablets in a blister card within a recyclable plastic dispenser. Each white tablet (debossed with “T 5 R” on one side and “Organon” on the other side) contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol. Each green tablet (debossed with “K 2 H” on one side and “Organon” on the other side) contains inert ingredients. Boxes of 6 NDC 0052-0261-06 Storage: Store below 86°F (30°C) only REFERENCES 1. Hatcher RA, Trussell J, Stewart F et al. Contraceptive Technology: Seventeenth Revised Edition, New York: Irvington Publishers, 1998. 2. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 1). N Engl J Med 1981; 305:612–618. 3. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med 1981; 305:672–677. 4. Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. 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Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med 1973; 288:871–878. 28. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234–236. 29. Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979; 2 (6203):1468–70. 30. Collaborative Group for the Study of Stroke in Young Women: Oral contraceptives and stroke in young women: associated risk factors. JAMA 1975; 231:718–722. 31. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970; 2:203–209. 32. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980; 280 (6224):1157–1161. 33. Kay CR. 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Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 1976; 124:573–577. 46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930. 47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long-term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339–344. 48. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Br Med J 1985; 209:961–965. 49. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644–648. 50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433–435. 51. Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386–394. 52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437–440. 53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355–1357. 54. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357–1361. 55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447–452. 56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 36 Gynecol 1981; 140:521–524. 57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. 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Am J Epidemiol 1984; 119:796–805. 64. Strom BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335–341. 65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045–1049. 66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In Progesterone and Progestin. Edited by Bardin CW, Milgrom E, Mauvis-Jarvis P. New York, Raven Press, 1983 pp. 395–410. 67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985; 38:857–864. 68. Royal College of General Practitioners’ Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624. 69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499–2503. 70. Laragh AJ. Oral contraceptive induced hypertension—nine years later. Am J Obstet Gynecol 1976; 126:141–147. 71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort. In Pharmacology of Steroid Contraceptive Drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977 pp. 277–288. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 37 (Monographs of the Mario Negri Institute for Pharmacological Research, Milan). 72. Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140–143. 73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596–1599. 74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796–800. 75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68–69. 76. Ory HW, Cole P, Macmahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419– 422. 77. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182–184. 78. Ory HW, Forrest JD, Lincoln R. Making Choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p. 1. 79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast Cancer in relation to early use of oral contraceptives 1988; 259:1828–1833. 80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-controlled study of oral contraceptive use and breast cancer. JNCI 1984; 72:39–42. 81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br. J. Cancer 1986; 54:311–317. 82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use in breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650–654. 83. Kay CR, Hannaford PC. Breast cancer and the pill—A further report from the Royal College of General Practitioners’ oral contraception study. Br. J. Cancer 1988; 58:675–680. 84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287–299. 85. 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N Engl J Med 1990; 323:1375–81. 91. Kloosterboer, HJ et al. Selectivity in progesterone and androgen receptor binding of progestogens used in oral contraception. Contraception, 1988; 38:325–32. 92. Van der Vies, J and de Visser, J. Endocrinological studies with desogestrel. Arzneim. Forsch./Drug Res., 1983; 33(l),2:231–6. 93. Data on file, Organon Inc. 94. Fotherby, K. Oral contraceptives, lipids and cardiovascular diseases. Contraception, 1985; Vol. 31; 4:367–94. 95. Lawrence, DM et al. Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne. Clinical Endocrinology, 1981; 15:87–91. 96. Cullberg, G et al. Effects of a low-dose desogestrel-ethinyl estradiol combination on hirsutism, androgens and sex hormone binding globulin in women with a polycystic ovary syndrome. Acta Obstet Gynecol Scand, 1985; 64:195–202. 97. Jung-Hoffmann, C and Kuhl, H. Divergent effects of two low-dose oral contraceptives on sex hormone-binding globulin and free testosterone. AJOG, 1987; 156:199–203. 98. Hammond, G et al. Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel. Fertil. Steril., 1984; 42:44–51. 99. Palatsi, R et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol, 1984; 64:517–23. 100. Porter JB, Hunter J, Jick H et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985; 66:1–4. 101. Porter JB, Jick H, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987; 7029–32. 102. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and non-fatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet, 1995; 346:1589–93. 103. World Health Organization Collaborative Study of Cardiovascular Disease and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 39 Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet, 1995; 346:1582–88. 104. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD on behalf of Transnational Research Group on Oral Contraceptives and Health of Young Women. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Br Med J, 1996; 312:83–88. PATIENT PACKAGE INSERT BRIEF SUMMARY Desogen® (desogestrel and ethinyl estradiol) Tablets This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Oral contraceptives, also known as “birth control pills” or “the pill”, are taken to prevent pregnancy. When taken correctly, oral contraceptives have a failure rate of about 1% per year (1 pregnancy per 100 women per year of use) when used without missing any pills. The typical failure rate of large numbers of pill users is less than 5% per year (5 pregnancies per 100 women per year of use) when women who miss pills are included. Forgetting to take pills increases the chances of pregnancy. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: • smoke • have high blood pressure, diabetes, high cholesterol • have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 40 You should not take the pill if you are pregnant or have unexplained vaginal bleeding. Although cardiovascular disease risks may increase with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding or spotting between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are young and in good health. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis) or lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), and blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes, and subsequent serious medical consequences. Women with migraine headaches also may be at increased risk of stroke when taking the pill. 2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 41 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed leaflet (DETAILED PATIENT PACKAGE INSERT) given to you with your supply of pills. Notify your doctor or health care provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants, some antibiotics, and herbal preparations containing St. John’s Wort (hypericum perforatum) may decrease oral contraceptive effectiveness. Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that women taking the pill are examined more often, so that breast cancer is more likely to be detected. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use the pill. However, this finding may be related to factors other than the use of the pill. Taking the pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your doctor or health care provider. Your doctor or health care provider will take a medical and family history and may examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 42 and your doctor or health care provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your doctor or health care provider. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. INSTRUCTIONS TO PATIENTS HOW TO TAKE DESOGEN® IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: • Before you start taking your pills • Anytime you are not sure what to do 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1–3 PACKS OF PILLS. If you have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your doctor or health care provider. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 43 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE CERTAIN MEDICINES, including some antibiotics or the herbal supplement St. John's Wort, your pills may not work as well. Use a back-up method (such as condoms, spermicides, or diaphragm) until you check with your doctor or health care provider. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or health care provider about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or health care provider. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK: IT WILL HAVE 28 PILLS: This 28-pill pack has 21 “active” [white] pills (with hormones) for Weeks 1, 2, and 3 and 7 “inactive” green pills (without hormones) for Week 4. 3. ALSO FIND: • where on the pack to start taking the pills, • in what order to take the pills (follow the arrows), and • the week numbers as shown in the picture below. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 44 4. BE SURE YOU HAVE READY AT ALL TIMES: • ANOTHER KIND OF BIRTH CONTROL (such as condoms, spermicides, or diaphragm) to use as a back-up in case you miss pills. • AN EXTRA, FULL PILL PACK OF DESOGEN®. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or health care provider which is the best day for you. Pick a time of day which will be easy to remember. DAY 1 START: 1. Pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins). 2. Place this day label strip in the cycle tablet dispenser over the area that has the days of the week (starting with Sunday) imprinted in the plastic. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 45 Note: If the first day of your period is a Sunday, you can skip steps #1 and #2. 3. Take the first “active” [white] pill of the first pack during the first 24 hours of your period. 4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first “active” [white] pill of the first pack on the first Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms, spermicides, or a diaphragm are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 46 Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 “active” [white] pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 “active” [white] pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you restart your pills. You MUST use another birth control method (such as condoms, spermicides, or diaphragm) as a back-up method for those 7 days. If you MISS 2 “active” [white] pills in a row in WEEK 3: 1. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 47 On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or health care provider because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you restart your pills. You MUST use another birth control method (such as condoms, spermicides, or diaphragm) as a back- up method for those 7 days. If you MISS 3 OR MORE “active” [white] pills in a row (during the first 3 weeks): 1. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your doctor or health care provider because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex on the days when you missed pills or during the first 7 days after restarting your pills. You MUST use another birth control method (such as condoms, spermicides, or diaphragm) as a back-up method the next time you have sex and for the first 7 days after you restart your pills. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 48 IF YOU FORGET ANY OF THE 7 “INACTIVE” [GREEN] PILLS IN WEEK 4: 1. THROW AWAY the pills you missed. 2. Keep taking 1 pill each day until the pack is empty. 3. You do not need to use a back-up method of birth control. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: 1. Use a BACK-UP METHOD of birth control anytime you have sex. 2. KEEP TAKING ONE “ACTIVE” [WHITE] PILL EACH DAY until you can reach your doctor or health care provider. DETAILED PATIENT PACKAGE INSERT Desogen® (desogestrel and ethinyl estradiol) Tablets This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases. only PLEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully. DESCRIPTION Desogen® contains a combination of a progestin and estrogen, the two kinds of female hormones. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 49 Each white tablet contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol. Each green tablet contains inert ingredients. INTRODUCTION Any woman who considers using oral contraceptives (the birth control pill or the pill) should understand the benefits and risks of using this form of birth control. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your doctor or health care provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your doctor’s or health care provider’s advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy and are more effective than other non-surgical methods of birth control. When they are taken correctly, without missing any pills, the chance of becoming pregnant is about 1% (1 pregnancy per 100 women per year of use). Typical failure rates, including women who do not always take the pills exactly as directed, are actually 5% (5 pregnancies per 100 women per year of use). The chance of becoming pregnant increases with each missed pill during a menstrual cycle. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50 In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: No methods: 85% Spermicides alone: 26% Periodic abstinence: 25% Withdrawal: 19% Cervical Cap with spermicides: 20 to 40% Vaginal sponge: 20 to 40% Diaphragm with spermicides: 20% Condom alone (female): 21% Condom alone (male): 14% IUD: less than 1 to 2% Implants: less than 1% Injectable progestogen: less than 1% Male sterilization: less than 1% Female sterilization: less than 1% WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 51 Some women should not use the pill. For example, you should not take the pill if you are pregnant or think you may be pregnant. You should also not use the pill if you have any of the following conditions: • A history of heart attack or stroke • A history of blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes • A history of blood clots in the deep veins of your legs • Chest pain (angina pectoris) • Severe high blood pressure • Diabetes with complications of the kidneys, eyes, nerves, or blood vessels • Headaches with neurological symptoms • Known or suspected breast cancer or cancer of the lining of the uterus, cervix, or vagina (now or in the past) • Unexplained vaginal bleeding (until a diagnosis is reached by your health care provider) • Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of hormonal birth control of any kind (the pill, patch, vaginal ring, injection, or implant) • Liver tumor (benign or cancerous) • Heart valve or heart rhythm disorders that may be associated with formation of blood clots • Need for a long period of bed rest following major surgery • Known or suspected pregnancy • Active liver disease with abnormal liver function tests • An allergy or hypersensitivity to any of the components of Desogen®. Tell your doctor or health care provider if you have ever had any of these conditions. Your doctor or health care provider can recommend another method of birth control. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 52 OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your doctor or health care provider if you have: • Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram • Diabetes • Elevated cholesterol or triglycerides • High blood pressure • Migraine or other headaches or epilepsy • Depression • Gallbladder, liver, heart, or kidney disease • Scanty or irregular menstrual periods Women with any of these conditions should be checked often by their doctor or health care provider if they choose to use oral contraceptives. Talk to your healthcare provider about using Desogen® if you: • Smoke • Recently had a baby • Recently had a miscarriage or abortion • Are breastfeeding • Are taking any other medications This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 53 RISKS OF TAKING ORAL CONTRACEPTIVES 1. Risk of developing blood clots Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the leg can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blockage of the vessel carrying blood to the lungs. The risks of these side effects may be greater with desogestrel-containing oral contraceptives such as Desogen® (desogestrel and ethinyl estradiol) Tablets than with certain other low- dose pills. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your doctor or health care provider about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breast-feeding. If you are breast-feeding, you should wait until you have weaned your child before using the pill (see the section on Breast Feeding in GENERAL PRECAUTIONS). The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for a number of years after stopping oral contraceptives. The risk of venous thromboembolic disease associated with oral contraceptives does not increase with length of use and disappears after pill use is stopped. The risk of abnormal blood clotting increases with age in both users and non-users of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44 it is estimated that about 1 in 2000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among non-users in the same age group, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 54 about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for non-users the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2500 per year for oral contraceptive users and about 1 in 10,000 per year for non-users. 2. Heart attacks and strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. Women with migraine (especially migraine with aura) who take oral contraceptives also may be at a higher risk of stroke. 3. Gallbladder disease Oral contraceptive users probably have a greater risk than non-users of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver tumors In rare cases, oral contraceptives can cause benign, but dangerous, liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, a possible, but not definite, association has been found with the pill and liver cancers in two studies, in which a few women who developed these very rare cancers were found to have used oral contraceptives for long periods. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 55 5. Cancer of the reproductive organs and breasts Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that women taking the pill are examined more often, so that breast cancer is more likely to be detected. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that pills may cause such cancers. 6. Lipid metabolism and inflammation of the pancreas In patients with inherited defects of lipid metabolism, there have been reports of significant elevations of plasma triglycerides during estrogen therapy. This has led to pancreatitis in some cases. ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 56 ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15–19 20–24 25–29 30–34 35–39 40–44 No fertility control methods* 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 non-smoker Oral contraceptives 2.2 3.4 6.6 13.5 51.1 117.2 smoker IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth related ** Deaths are method related In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7–26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death is always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 57 number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117 per 100,000 women) than the estimated risk associated with pregnancy (28 per 100,000 women) in that age group. The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older, high-dose pills and on less selective use of pills than is practiced today. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. However, all women, especially older women, are cautioned to use the lowest dose pill that is effective. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your doctor or health care provider immediately: • Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) • Pain in the calf (indicating a possible clot in the leg) • Crushing chest pain or heaviness in the chest (indicating a possible heart attack) • Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) • Sudden partial or complete loss of vision (indicating a possible clot in the eye) • Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or health care provider to show you how to examine your breasts) • Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) • Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 58 • Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems). SIDE EFFECTS OF ORAL CONTRACEPTIVES In addition to the risks and more serious side effects discussed above (see RISKS OF TAKING ORAL CONTRACEPTIVES, ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY and WARNING SIGNALS sections), the following may also occur: 1. Irregular vaginal bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding, which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your doctor or health care provider. 2. Contact lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your doctor or health care provider. 3. Fluid retention or raised blood pressure Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your doctor or health care provider. 4. Melasma A spotty darkening of the skin is possible, particularly of the face. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 59 5. Other side effects Other side effects may include nausea and vomiting, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, and vaginal infections. If any of these side effects bother you, call your doctor or health care provider. GENERAL PRECAUTIONS 1. Missed periods and use of oral contraceptives before or during early pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your doctor or health care provider before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your doctor or health care provider immediately to determine whether you are pregnant. Stop taking Desogen® if you are pregnant. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these studies have not been confirmed. Nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly necessary and prescribed by your doctor or health care provider. You should check with your doctor or health care provider about risks to your unborn child of any medication taken during pregnancy. 2. While breast-feeding If you are breast-feeding, consult your doctor health care provider before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 60 contraceptives while breast-feeding. You should use another method of contraception since breast-feeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breast-feed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely. 3. Laboratory tests If you are scheduled for any laboratory tests, tell your doctor or health care provider you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital), topiramate (Topamax®), carbamazepine (Tegretol® is one brand of this drug), phenytoin (Dilantin® is one brand of this drug), phenylbutazone (Butazolidin® is one brand), herbal products containing St. John’s Wort (hypericum perforatum), and possibly certain antibiotics. You may need to use additional contraception when you take drugs which can make oral contraceptives less effective. Be sure to tell your doctor or health care provider if you are taking or start taking any medications while taking birth control pills. 5. Sexually transmitted diseases This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 61 HOW TO TAKE DESOGEN® IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: • Before you start taking your pills. • Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1–3 PACKS OF PILLS. If you have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your doctor health care provider. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE CERTAIN MEDICINES, including some antibiotics or the herbal supplement St. John’s Wort, your pills may not work as well. Use a back-up method (such as condoms, spermicides, or diaphragm) until you check with your doctor or health care provider. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 62 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or health care provider about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or health care provider. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK: IT WILL HAVE 28 PILLS: This 28-pill pack has 21 “active” [white] pills (with hormones) for Weeks 1, 2, and 3 and 7 “inactive” green pills (without hormones) for Week 4. 3. ALSO FIND: • where on the pack to start taking the pills, • in what order to take the pills (follow the arrows), and • the week numbers as shown in the picture below. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 63 4. BE SURE YOU HAVE READY AT ALL TIMES: • ANOTHER KIND OF BIRTH CONTROL (such as condoms, spermicides, or diaphragm) to use as a back-up in case you miss pills. • AN EXTRA, FULL PILL PACK OF DESOGEN®. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or health care provider which is the best day for you. Pick a time of day which will be easy to remember. DAY 1 START: 1. Pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins). 2. Place this day label strip in the cycle tablet dispenser over the area that has the days of the week (starting with Sunday) imprinted in the plastic. Note: If the first day of your period is a Sunday, you can skip steps #1 and #2. 3. Take the first “active” [white] pill of the first pack during the first 24 hours of your period. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 64 4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first “active” [white] pill of the first pack on the first Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms, spermicides, or a diaphragm are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 “active” [white] pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 65 If you MISS 2 “active” [white] pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you restart your pills. You MUST use another birth control method (such as condoms, spermicides, or a diaphragm) as a back-up method for those 7 days. If you MISS 2 “active” [white] pills in a row in WEEK 3: 1. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or health care provider because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you restart your pills. You MUST use another birth control method (such as condoms, spermicides, or diaphragm) as a back- up method for those 7 days. If you MISS 3 OR MORE “active” [white] pills in a row (during the first 3 weeks): 1. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 66 If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or health care provider because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex on the days when you missed pills or during the fist 7 days after restarting your pills. You MUST use another birth control method (such as condoms, spermicides, or diaphragm) as a back-up method the next time you have sex and for the first 7 days after restarting your pills. IF YOU FORGET ANY OF THE 7 “INACTIVE” [GREEN] PILLS IN WEEK 4: 1. THROW AWAY the pills you missed. 2. Keep taking 1 pill each day until the pack is empty. 3. You do not need to use a back-up method of birth control. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: 1. Use a BACK-UP METHOD of birth control anytime you have sex. 2. KEEP TAKING ONE “ACTIVE” [WHITE] PILL EACH DAY until you can reach your doctor or health care provider. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 67 ADDITIONAL INFORMATION 1. PREGNANCY DUE TO PILL FAILURE The incidence of pill failure resulting in pregnancy is approximately one percent (i.e., one pregnancy per 100 women per year of use) if taken every day as directed, but more typical failure rates are about 5% (5 pregnancies per 100 women per year of use). If failure does occur, the risk to the fetus is minimal. 2. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. 3. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your doctor or health care provider or pharmacist. 4. OTHER INFORMATION Your doctor or health care provider will take a medical and family history and may examine you before prescribing an oral contraceptive. The physical examination may be delayed to another time if you request it and your doctor or the health care provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your doctor or health care provider if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 68 appointments with your doctor or health care provider, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of combination oral contraceptives may provide certain benefits. They are: • menstrual cycles may become more regular. • blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur. • pain or other symptoms during menstruation may be encountered less frequently. • ectopic (tubal) pregnancy may occur less frequently. • non-cancerous cysts or lumps in the breast may occur less frequently. • acute pelvic inflammatory disease may occur less frequently. • oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your doctor, health care provider or pharmacist. They have a more technical leaflet called the Prescribing Information, which you may wish to read. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 69 Manufactured for Organon USA Inc. Roseland, NJ 07068 by N.V. Organon, Oss, The Netherlands or Organon (Ireland) Ltd., Swords, Co. Dublin, Ireland ©2004 Organon USA Inc. 5310130 11/13/06 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:40.252829	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020071s017lbl.pdf', 'application_number': 20071, 'submission_type': 'SUPPL ', 'submission_number': 17}
12,181	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Charles Ganley 7/15/02 05:50:16 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:40.316242	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20076s21lbl.pdf', 'application_number': 20076, 'submission_type': 'SUPPL ', 'submission_number': 21}
12,180	LIORESAL® INTRATHECAL (baclofen injection) Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death. Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. Special attention should be given to patients at apparent risk (e.g. spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information (see WARNINGS). DESCRIPTION LIORESAL INTRATHECAL (baclofen injection) is a muscle relaxant and antispastic. Its chemical name is 4- amino- 3-( 4- chlorophenyl) butanoic acid, and its structural formula is: structural formula Baclofen is a white to off- white, odorless or practically odorless crystalline powder, with a molecular weight of 213.66. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform. LIORESAL INTRATHECAL is a sterile, pyrogen-free, isotonic solution free of antioxidants, preservatives or other potentially neurotoxic additives indicated only for intrathecal administration. The drug is stable in solution at 37° C and compatible with CSF. Each milliliter of LIORESAL INTRATHECAL contains baclofen U. S. P. 50 mcg, 500 mcg or 2000 mcg and sodium chloride 9 mg in Water for Injection; pH range is 5.0 - 7.0. Each ampule is intended for SINGLE USE ONLY. Discard any unused portion. DO NOT AUTOCLAVE. CLINICAL PHARMACOLOGY The precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype. Reference ID: 3039097 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LIORESAL INTRATHECAL when introduced directly into the intrathecal space permits effective CSF concentrations to be achieved with resultant plasma concentrations 100 times less than those occurring with oral administration. In people, as well as in animals, baclofen has been shown to have general CNS depressant prop- erties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression. Pharmacodynamics of LIORESAL INTRATHECAL: Intrathecal Bolus: Adult Patients: The onset of action is generally one-half hour to one hour after an intrathecal bolus. Peak spasmolytic effect is seen at approximately four hours after dosing and effects may last four to eight hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms. Pediatric Patients: The onset, peak response and duration of action is similar to those seen in adult patients. Continuous Infusion: LIORESAL INTRATHECAL’S antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum activity is observed in 24 to 48 hours. Continuous Infusion: No additional information is available for pediatric patients. Pharmacokinetics of LIORESAL INTRATHECAL: The pharmacokinetics of CSF clearance of LIORESAL INTRATHECAL calculated from intrathecal bolus or continuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF. Intrathecal Bolus: After a bolus lumbar injection of 50 or 100 mcg LIORESAL INTRATHECAL in seven patients, the average CSF elimination half-life was 1.51 hours over the first four hours and the average CSF clearance was approximately 30 mL/ hour. Continuous Infusion: The mean CSF clearance for LIORESAL INTRATHECAL (baclofen injection) was approximately 30 mL/ hour in a study involving ten patients on continuous intrathecal infusion. Concurrent plasma concentrations of baclofen during intrathecal administration are expected to be low (0- 5 ng/ mL). Limited pharmacokinetic data suggest that a lumbar-cisternal concentration gradient of about 4: 1 is established along the neuroaxis during baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap in 5 patients receiving continuous baclofen infusion at the lumbar level at doses associated with therapeutic efficacy; the interpatient variability was great. The gradient was not altered by position. Six pediatric patients (age 8- 18 years) receiving continuous intrathecal baclofen infusion at doses of 77- 400 mcg/ day had plasma baclofen levels near or below 10 ng/ mL. INDICATIONS LIORESAL INTRATHECAL is indicated for use in the management of severe spasticity. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of LIORESAL INTRATHECAL via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy. LIORESAL INTRATHECAL (baclofen injection) is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifically for the administration of LIORESAL INTRATHECAL into the intrathecal space. Spasticity of Spinal Cord Origin: Evidence supporting the efficacy of LIORESAL INTRATHECAL was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of LIORESAL INTRATHECAL to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. LIORESAL INTRATHECAL was superior to placebo on both principal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms. Spasticity of Cerebral Origin: The efficacy of LIORESAL INTRATHECAL was investigated in three controlled clinical trials; two enrolled patients with cerebral palsy and one enrolled patients with spasticity Reference ID: 3039097 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda due to previous brain injury. The first study, a randomized controlled cross- over trial of 51 patients with cerebral palsy, provided strong, statistically significant results; LIORESAL INTRATHECAL was superior to placebo in reducing spasticity as measured by the Ashworth Scale. A second cross- over study was conducted in 11 patients with spasticity arising from brain injury. Despite the small sample size, the study yielded a nearly significant test statistic (p= 0.066) and provided directionally favorable results. The last study, however, did not provide data that could be reliably analyzed. LIORESAL INTRATHECAL therapy may be considered an alternative to destructive neurosurgical procedures. Prior to implantation of a device for chronic intrathecal infusion of LIORESAL INTRATHECAL, patients must show a response to LIORESAL INTRATHECAL in a screening trial (see Dosage and Administration). CONTRAINDICATIONS Hypersensitivity to baclofen. LIORESAL INTRATHECAL is not recommended for intravenous, intramuscular, subcutaneous or epidural administration. WARNINGS LIORESAL INTRATHECAL is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) and in implantable pumps approved by the FDA specifically for the intrathecal administration of baclofen. Because of the possibility of potentially life- threatening CNS depression, cardiovascular collapse, and/ or respiratory failure, physicians must be adequately trained and educated in chronic intrathecal infusion therapy. The pump system should not be implanted until the patient’s response to bolus LIORESAL INTRATHECAL injection is adequately evaluated. Evaluation (consisting of a screening procedure: see Dosage and Administration) requires that LIORESAL INTRATHECAL be administered into the intrathecal space via a catheter or lumbar puncture. Because of the risks associated with the screening procedure and the adjustment of dosage following pump implantation, these phases must be conducted in a medically supervised and adequately equipped environment following the instructions outlined in the Dosage and Administration section. Resuscitative equipment should be available. Following surgical implantation of the pump, particularly during the initial phases of pump use, the patient should be monitored closely until it is certain that the patient’s response to the infusion is acceptable and reasonably stable. On each occasion that the dosing rate of the pump and/ or the concentration of LIORESAL INTRATHECAL (baclofen injection) in the reservoir is adjusted, close medical monitoring is required until it is certain that the patient’s response to the infusion is acceptable and reasonably stable. It is mandatory that the patient, all patient caregivers, and the physicians responsible for the patient receive adequate information regarding the risks of this mode of treatment. All medical personnel and caregivers should be instructed in 1) the signs and symptoms of overdose, 2) procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site. Overdose: Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/ or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral pro- gression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction, inadvertent subcutaneous injection, or dosing error. (See Drug Overdose Symptoms and Treatment.) Extreme caution must be used when filling an FDA approved implantable pump. Such pumps should only be refilled through the reservoir refill septum. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Some pumps are also equipped with a catheter access port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port or inadvertent injection into the subcutaneous tissue may cause a life-threatening overdose. Withdrawal: Abrupt withdrawal of intrathecal baclofen, regardless of the cause, has resulted in sequelae that included high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that in rare cases progressed to rhabdomyolysis, multiple organ-system failure, and death. In the first 9 years of Reference ID: 3039097 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six patients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Common reasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir, and end of pump battery life; human error may have played a causal or contributing role in some cases. Cases of intrathecal mass at the tip of the implanted catheter leading to withdrawal symptoms have also been reported, most of them involving pharmacy compounded analgesic admixtures (see PRECAUTIONS). Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal. Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic- malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis. Rapid, accurate diagnosis and treatment in an emergency-room or intensive- care setting are important in order to prevent the potentially life-threatening central nervous system and systemic effects of intrathecal baclofen withdrawal. The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist drugs such as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal. Seizures have been reported during overdose and with withdrawal from LIORESAL INTRATHECAL as well as in patients maintained on therapeutic doses of LIORESAL INTRATHECAL. Fatalities : Spasticity of Spinal Cord Origin: There were 16 deaths reported among the 576 U.S. patients treat- ed with LIORESAL INTRATHECAL (baclofen injection) in pre- and post- marketing studies evaluated as of December 1992. Because these patients were treated under uncontrolled clinical settings, it is impossible to determine definitively what role, if any, LIORESAL INTRATHECAL played in their deaths. As a group, the patients who died were relatively young (mean age was 47 with a range from 25 to 63), but the majority suffered from severe spasticity of many years duration, were nonambulatory, had various medical complications such as pneumonia, urinary tract infections, and decubiti, and/ or had received multiple concomitant medications. A case- by- case review of the clinical course of the 16 patients who died failed to reveal any unique signs, symptoms, or laboratory results that would suggest that treatment with LIORESAL INTRATHECAL caused their deaths. Two patients, however, did suffer sudden and unexpected death within 2 weeks of pump implantation and one patient died unexpectedly after screening. One patient, a 44 year-old male with MS, died in hospital on the second day following pump implantation. An autopsy demonstrated severe fibrosis of the coronary conduction system. A second patient, a 52 year-old woman with MS and a history of an inferior wall myocardial infarction, was found dead in bed 12 days after pump implantation, 2 hours after having had documented normal vital signs. An autopsy revealed pulmonary congestion and bilateral pleural effusions. It is impossible to determine whether LIORESAL INTRATHECAL contributed to these deaths. The third patient underwent three baclofen screening trials. His medical history included SCI, aspiration pneumonia, septic shock, disseminated intravascular coagulopathy, severe metabolic acidosis, hepatic toxicity, and status epilepticus. Twelve days after screening (he was not implanted), he again experienced status epilepticus with subsequent significant neurological deterioration. Based upon prior instruction, extraordinary resuscitative measures were not pursued and the patient died. Spasticity of Cerebral Origin: There were three deaths occurring among the 211 patients treated with LIORESAL INTRATHECAL in pre- marketing studies as of March 1996. These deaths were not attributed to the therapy. PRECAUTIONS Reference ID: 3039097 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Children should be of sufficient body mass to accommodate the implantable pump for chronic infu- sion. Please consult pump manufacturer's manual for specific recommendations. Safety and effectiveness in pediatric patients below the age of 4 have not been established. Screening Patients should be infection-free prior to the screening trial with LIORESAL INTRATHECAL (baclofen injection) because the presence of a systemic infection may interfere with an assessment of the patient’s response to bolus LIORESAL INTRATHECAL. Pump Implantation Patients should be infection-free prior to pump implantation because the presence of infection may increase the risk of surgical complications. Moreover, a systemic infection may complicate dosing. Pump Dose Adjustment and Titration In most patients, it will be necessary to increase the dose gradually over time to maintain effec- tiveness; a sudden requirement for substantial dose escalation typically indicates a catheter compli- cation (i. e., catheter kink or dislodgement). Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Subcutaneous injection may result in symptoms of a systemic overdose or early depletion of the reservoir. Refill intervals should be carefully calculated to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possibly symptoms of withdrawal. Strict aseptic technique in filling is required to avoid bacterial contamination and serious infection. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir. Extreme caution must be used when filling an FDA approved implantable pump equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the catheter access port may cause a life-threatening overdose. Additional considerations pertaining to dosage adjustment: It may be important to titrate the dose to maintain some degree of muscle tone and allow occasional spasms to: 1) help support circulatory function, 2) possibly prevent the formation of deep vein thrombosis, 3) optimize activities of daily living and ease of care. Except in overdose related emergencies, the dose of LIORESAL INTRATHECAL should ordinarily be reduced slowly if the drug is discontinued for any reason. An attempt should be made to discontinue concomitant oral antispasticity medication to avoid possible overdose or adverse drug interactions, either prior to screening or following implant and initiation of chronic LIORESAL INTRATHECAL infusion. Reduction and discontinuation of oral anti-spasmotics should be done slowly and with careful monitoring by the physician. Abrupt reduction or discontinuation of concomitant antispastics should be avoided. Drowsiness: Drowsiness has been reported in patients on LIORESAL INTRATHECAL. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system depressant effects of LIORESAL INTRATHECAL (baclofen injection) may be additive to those of alcohol and other CNS depressants. Intrathecal mass: Cases of intrathecal mass at the tip of the implanted catheter have been reported, most of them involving pharmacy compounded analgesic admixtures. The most frequent symptoms associated with intrathecal mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. In patients with new neurological signs or symptoms suggestive of an intrathecal mass, consider a neurosurgical consultation, since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an intrathecal mass. Reference ID: 3039097 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Precautions in special patient populations: Careful dose titration of LIORESAL INTRATHECAL is needed when spasticity is necessary to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function and care. Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with LIORESAL INTRATHECAL and kept under careful surveillance, because exacerbations of these conditions have been observed with oral administration. LIORESAL INTRATHECAL should be used with caution in patients with a history of autonomic dys- reflexia. The presence of nociceptive stimuli or abrupt withdrawal of LIORESAL INTRATHECAL (baclofen injection) may cause an autonomic dysreflexic episode. Because LIORESAL is primarily excreted unchanged by the kidneys, it should be given with caution in patients with impaired renal function and it may be necessary to reduce the dosage. LABORATORY TESTS No specific laboratory tests are deemed essential for the management of patients on LIORESAL INTRATHECAL. DRUG INTERACTIONS There is inadequate systematic experience with the use of LIORESAL INTRATHECAL in combina tion with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of LIORESAL INTRATHECAL and epidural morphine include hypotension and dyspnea. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY No increase in tumors was seen in rats receiving LIORESAL (baclofen USP) orally for two years at approximately 30- 60 times on a mg/ kg basis, or 10- 20 times on a mg/ m2 basis, the maximum oral dose recommended for human use. Mutagenicity assays with LIORESAL have not been performed. PREGNANCY CATEGORY C LIORESAL (baclofen USP) given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/ kg basis, or 3 times on a mg/m2 basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits. There are no adequate and well-controlled studies in pregnant women. LIORESAL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. NURSING MOTHERS In mothers treated with oral LIORESAL (baclofen USP) in therapeutic doses, the active substance passes into the breast milk. It is not known whether detectable levels of drug are present in breast milk of nursing mothers receiving LIORESAL INTRATHECAL. As a general rule, nursing should be undertaken while a patient is receiving LIORESAL INTRATHECAL only if the potential benefit justifies the potential risks to the infant. PEDIATRIC USE Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer's manual for specific recommendations. Safety and effectiveness in pediatric patients below the age of 4 have not been established. Considerations based on experience with oral LIORESAL (baclofen USP) A dose- related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral LIORESAL. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral LIORESAL for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population. ADVERSE DRUG EVENTS Spasticity of Spinal Cord Origin: Commonly Observed in Patients with Spasticity of Spinal Origin — In pre- and post- marketing clin- ical trials, the most commonly observed adverse events associated with use of LIORESAL INTRATHECAL (baclofen injection) which were not seen at an equivalent incidence among placebo- treated patients were: somnolence, dizziness, nausea, hypotension, headache, convulsions and hypotonia. Associated with Discontinuation of Treatment — 8/ 474 patients with spasticity of spinal cord origin receiving long term infusion of LIORESAL INTRATHECAL in pre- and post- marketing clinical studies in Reference ID: 3039097 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the U. S. discontinued treatment due to adverse events. These include: pump pocket infections (3), meningitis (2), wound dehiscence (1), gynecological fibroids (1) and pump overpressurization (1) with unknown, if any, sequela. Eleven patients who developed coma secondary to overdose had their treatment temporarily suspended, but all were subsequently re-started and were not, therefore, con- sidered to be true discontinuations. Fatalities — See Warnings. Incidence in Controlled Trials — Experience with LIORESAL INTRATHECAL (baclofen injection) obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies were of very brief duration (up to three days of infusion) and involved only a total of 63 patients. The following events occurred among the 31 patients receiving LIORESAL INTRATHECAL (baclofen injection) in two randomized, placebo- controlled trials: hypotension (2), dizziness (2), headache (2), dyspnea (1). No adverse events were reported among the 32 patients receiving placebo in these studies. Events Observed during the Pre- and Post- marketing Evaluation of LIORESAL INTRATHECAL — Adverse events associated with the use of LIORESAL INTRATHECAL reflect experience gained with 576 patients followed prospectively in the United States. They received LIORESAL INTRATHECAL for periods of one day (screening) (N = 576) to over eight years (maintenance) (N = 10). The usual screening bolus dose administered prior to pump implantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of LIORESAL INTRATHECAL cannot be reliably assessed in many cases and many of the adverse events reported are known to occur in association with the underlying conditions being treated. Nonetheless, many of the more commonly reported reactions— hypotonia, somnolence, dizziness, paresthesia, nausea/vomiting and headache— appear clearly drug-related. Adverse experiences reported during all U.S. studies (both controlled and uncontrolled) are shown in the following table. Eight of 474 patients who received chronic infusion via implanted pumps had adverse experiences which led to a discontinuation of long term treatment in the pre- and post- marketing studies. Reference ID: 3039097 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ________________________________________________________________________________ ________________________________________________________________________________ ____________________________________________________________________________________ INCIDENCE OF MOST FREQUENT (≥1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS Percent of Patients Reporting Events N = 576 N = 474 N = 430 Screeninga Titrationb Maintenancec Percent Percent Percent Adverse Event Hypotonia 5.4 13.5 25.3 Somnolence 5.7 5.9 20.9 Dizziness 1.7 1.9 7.9 Paresthesia 2.4 2.1 6.7 Nausea and Vomiting 1.6 2.3 5.6 Headache 1.6 2.5 5.1 Constipation 0.2 1.5 5.1 Convulsion 0.5 1.3 4.7 Urinary Retention 0.7 1.7 1.9 Dry Mouth 0.2 0.4 3.3 Accidental Injury 0.0 0.2 3.5 Asthenia 0.7 1.3 1.4 Confusion 0.5 0.6 2.3 Death 0.2 0.4 3.0 Pain 0.0 0.6 3.0 Speech Disorder 0.0 0.2 3.5 Hypotension 1.0 0.2 1.9 Ambylopia 0.5 0.2 2.3 Diarrhea 0.0 0.8 2.3 Hypoventilation 0.2 0.8 2.1 Coma 0.0 1.5 0.9 Impotence 0.2 0.4 1.6 Peripheral Edema 0.0 0.0 2.3 Urinary Incontinence 0.0 0.8 1.4 Insomnia 0.0 0.4 1.6 Anxiety 0.2 0.4 0.9 Depression 0.0 0.0 1.6 Dyspnea 0.3 0.0 1.2 Fever 0.5 0.2 0.7 Pneumonia 0.2 0.2 1.2 Urinary Frequency 0.0 0.6 0.9 Urticaria 0.2 0.2 1.2 Anorexia 0.0 0.4 0.9 Diplopia 0.0 0.4 0.9 Dysautonomia 0.2 0.2 0.9 Hallucinations 0.3 0.4 0.5 Hypertension 0.2 0.6 0.5 a Following administration of test bolus b Two month period following implant c Beyond two months following implant N= total number of patients entering each period %=% of patients evaluated In addition to the more common (1% or more) adverse events reported in the prospectively followed 576 domestic patients in pre- and post- marketing studies, experience from an additional 194 patients exposed to LIORESAL INTRATHECAL (baclofen injection) from foreign studies has been reported. The Reference ID: 3039097 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda following adverse events, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported: Nervous System: Abnormal gait, thinking abnormal, tremor, amnesia, twitching, vasodilitation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependence, incoordination, paranoid reaction and ptosis. Digestive System: Flatulence, dysphagia, dyspepsia and gastroenteritis. Cardiovascular: Postural hypotension, bradycardia, palpitations, syncope, arrhythmia ventricular, deep thrombophlebitis, pallor and tachycardia. Respiratory: Respiratory disorder, aspiration pneumonia, hyperventilation, pulmonary embolus and rhinitis. Urogenital: Hematuria and kidney failure. Skin and Appendages: Alopecia and sweating. Metabolic and Nutritional Disorders: Weight loss, albuminuria, dehydration and hyperglycemia. Special Senses: Abnormal vision, abnormality of accommodation, photophobia, taste loss and tinnitus. Body as a Whole: Suicide, lack of drug effect, abdominal pain, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome and overdose. Hemic and Lymphatic System: Anemia. Spasticity of Cerebral Origin: Commonly Observed — In pre- marketing clinical trials, the most commonly observed adverse events associated with use of LIORESAL INTRATHECAL (baclofen injection) which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia. Associated with Discontinuation of Treatment — Nine of 211 patients receiving LIORESAL INTRATHECAL in pre-marketing clinical studies in the U.S. discontinued long term infusion due to adverse events associated with intrathecal therapy. The nine adverse events leading to discontinuation were: infection (3), CSF leaks (2), meningitis (2), drainage (1), and unmanageable trunk control (1). Fatalities — Three deaths, none of which were attributed to LIORESAL INTRATHECAL, were reported in patients in clinical trials involving patients with spasticity of cerebral origin. See Warnings on other deaths reported in spinal spasticity patients. Incidence in Controlled Trials — Experience with LIORESAL INTRATHECAL (baclofen injection) obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following events occurred among the 62 patients receiving LIORESAL INTRATHECAL in two randomized, placebo-controlled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolence, leukocytosis, nausea, vomiting, nystagmus, chills, urinary retention, and hypotonia. Events Observed during the Pre- marketing Evaluation of LIORESAL INTRATHECAL — Adverse events associated with the use of LIORESAL INTRATHECAL reflect experience gained with a total of 211 U. S. patients with spasticity of cerebral origin, of whom 112 were pediatric patients (under age 16 at enrollment). They received LIORESAL INTRATHECAL for periods of one day (screening) (N= 211) to 84 months (maintenance) (N= 1). The usual screening bolus dose administered prior to pump implantation in these studies was 50- 75 mcg. The maintenance dose ranged from 22 mcg to 1400 mcg per day. Doses used in this patient population for long term infusion are generally lower than those required for patients with spasticity of spinal cord origin. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of LIORESAL INTRATHECAL cannot be reliably assessed in many cases. Nonetheless, many of the more commonly reported reactions— somnolence, dizziness, headache, nausea, hypotension, hypotonia and coma— appear clearly drug-related. The most frequent (≥1%) adverse events reported during all clinical trials are shown in the following table. Nine patients discontinued long term treatment due to adverse events. Reference ID: 3039097 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ____________________________________________________________________________ ____________________________________________________________________________________ INCIDENCE OF MOST FREQUENT (≥ 1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF CEREBRAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS Percent of Patients Reporting Events N = 211 N = 153 N = 150 Screeninga Titrationb Maintenancec Percent Percent Percent Adverse Event Hypotonia 2.4 14.4 34.7 Somnolence 7.6 10.5 18.7 Headache 6.6 7.8 10.7 Nausea and Vomiting 6.6 10.5 4.0 Vomiting 6.2 8.5 4.0 Urinary Retention 0.9 6.5 8.0 Convulsion 0.9 3.3 10.0 Dizziness 2.4 2.6 8.0 Nausea 1.4 3.3 7.3 Hypoventilation 1.4 1.3 4.0 Hypertonia 0.0 0.7 6.0 Paresthesia 1.9 0.7 3.3 Hypotension 1.9 0.7 2.0 Increased Salivation 0.0 2.6 2.7 Back Pain 0.9 0.7 2.0 Constipation 0.5 1.3 2.0 Pain 0.0 0.0 4.0 Pruritus 0.0 0.0 4.0 Diarrhea 0.5 0.7 2.0 Peripheral Edema 0.0 0.0 3.3 Thinking Abnormal 0.5 1.3 0.7 Agitation 0.5 0.0 1.3 Asthenia 0.0 0.0 2.0 Chills 0.5 0.0 1.3 Coma 0.5 0.0 1.3 Dry Mouth 0.5 0.0 1.3 Pneumonia 0.0 0.0 2.0 Speech Disorder 0.5 0.7 0.7 Tremor 0.5 0.0 1.3 Urinary Incontinence 0.0 0.0 2.0 Urination Impaired 0.0 0.0 2.0 a Following administration of test bolus b Two month period following implant c Beyond two months following implant N= Total number of patients entering each period. 211 patients received drug; (1 of 212) received placebo only. The more common (1% or more) adverse events reported in the prospectively followed 211 patients exposed to LIORESAL INTRATHECAL (baclofen injection) have been reported. In the total cohort, the following adverse events, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported: Nervous System: Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, halluci- nations, hysteria, insomnia, nystagmus, personality disorder, reflexes decreased, and vasodilitation. Reference ID: 3039097 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digestive System: Dysphagia, fecal incontinence, gastrointestinal hemorrhage and tongue disorder. Cardiovascular: Bradycardia. Respiratory: Apnea, dyspnea and hyperventilation. Urogenital: Abnormal ejaculation, kidney calculus, oliguria and vaginitis. Skin and Appendages: Rash, sweating, alopecia, contact dermatitis and skin ulcer. Special Senses: Abnormality of accommodation. Body as a Whole: Death, fever, abdominal pain, carcinoma, malaise and hypothermia. Hemic and Lymphatic System: Leukocytosis and petechial rash. DRUG OVERDOSE Special attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dose- titration phase of treatment, but also during re- introduction of LIORESAL INTRATHECAL after a period of interruption in therapy. Symptoms of LIORESAL INTRATHECAL Overdose: Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, hypothermia, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma of up to 72 hr. duration. In most cases reported, coma was reversible without sequelae after drug was discontinued. Symptoms of LIORESAL INTRATHECAL overdose were reported in a sensitive adult patient after receiving a 25 mcg intrathecal bolus. Treatment Suggestions for Overdose: There is no specific antidote for treating overdoses of LIORESAL INTRATHECAL (baclofen injection); however, the following steps should ordinarily be undertaken: 1) Residual LIORESAL INTRATHECAL solution should be removed from the pump as soon as possible. 2) Patients with respiratory depression should be intubated if necessary, until the drug is eliminated. If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30- 40 mL of CSF to reduce CSF baclofen concentration. DOSAGE AND ADMINISTRATION Refer to the manufacturer’s manual for the implantable pump approved for intrathecal infusion for specific instructions and precautions for programming the pump and/ or refilling the reservoir. There are various pumps with varying reservoir volumes and there are various refill kits available. It is important to be familiar with all of these products in order to select the appropriate refill kit for the particular pump in use. Screening Phase: Prior to pump implantation and initiation of chronic infusion of LIORESAL INTRATHECAL (baclofen injection), patients must demonstrate a positive clinical response to a LIORESAL INTRATHECAL bolus dose administered intrathecally in a screening trial. The screening trial employs LIORESAL INTRATHECAL at a concentration of 50 mcg/ mL. A 1 mL ampule (50 mcg/ mL) is available for use in the screening trial. The screening procedure is as follows. An initial bolus containing 50 micrograms in a volume of 1 milliliter is administered into the intrathecal space by barbotage over a period of not less than one minute. The patient is observed over the ensuing 4 to 8 hours. A positive response consists of a significant decrease in muscle tone and/ or frequency and/ or severity of spasms. If the initial response is less than desired, a second bolus injection may be administered 24 hours after the first. The second screening bolus dose consists of 75 micrograms in 1.5 milliliters. Again, the patient should be observed for an interval of 4 to 8 hours. If the response is still inadequate, a final bolus screening dose of 100 micrograms in 2 milliliters may be administered 24 hours later. Pediatric Patients: The starting screening dose for pediatric patients is the same as in adult patients, i.e., 50 mcg. However, for very small patients, a screening dose of 25 mcg may be tried first. Patients who do not respond to a 100 mcg intrathecal bolus should not be considered candidates for an implanted pump for chronic infusion. Post- Implant Dose Titration Period: To determine the initial total daily dose of LIORESAL INTRATHECAL following implant, the screening dose that gave a positive effect should be doubled and administered over a 24-hour period, unless the efficacy of the bolus dose was maintained for more than 8 hours, in which case the starting daily dose should be the screening dose delivered over a 24-hour period. No dose increases should be given in the first 24 hours (i.e., until the steady state is achieved). Reference ID: 3039097 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adult Patients with Spasticity of Spinal Cord Origin: After the first 24 hours, for adult patients, the daily dosage should be increased slowly by 10- 30% increments and only once every 24 hours, until the desired clinical effect is achieved. Adult Patients with Spasticity of Cerebral Origin: After the first 24 hours, the daily dose should be increased slowly by 5- 15% only once every 24 hours, until the desired clinical effect is achieved. Pediatric Patients: After the first 24 hours, the daily dose should be increased slowly by 5-15% only once every 24 hours, until the desired clinical effect is achieved. If there is not a substantive clinical response to increases in the daily dose, check for proper pump function and catheter patency. Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and dose- titration period immediately following implant. Resuscitative equipment should be immediately available for use in case of life- threatening or intolerable side effects. Maintenance Therapy: Spasticity of Spinal Cord Origin Patients: The clinical goal is to maintain muscle tone as close to normal as possible, and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects. Very often, the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in life style due to the alleviation of spasticity. During periodic refills of the pump, the daily dose may be increased by 10-40%, but no more than 40%, to maintain adequate symptom control. The daily dose may be reduced by 10-20% if patients experience side effects. Most patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement). Maintenance dosage for long term continuous infusion of LIORESAL INTRATHECAL (baclofen injection) has ranged from 12 mcg/ day to 2003 mcg/ day, with most patients adequately maintained on 300 micrograms to 800 micrograms per day. There is limited experience with daily doses greater than 1000 mcg/ day. Determination of the optimal LIORESAL INTRATHECAL dose requires individual titration. The lowest dose with an optimal response should be used. Spasticity of Cerebral Origin Patients: The clinical goal is to maintain muscle tone as close to nor- mal as possible and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects, or to titrate the dose to the desired degree of muscle tone for optimal functions. Very often the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in life style due to the alleviation of spasticity. During periodic refills of the pump, the daily dose may be increased by 5 - 20%, but no more than 20%, to maintain adequate symptom control. The daily dose may be reduced by 10-20% if patients experience side effects. Many patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement). Maintenance dosage for long term continuous infusion of LIORESAL INTRATHECAL (baclofen injection) has ranged from 22 mcg/ day to 1400 mcg/ day, with most patients adequately maintained on 90 micrograms to 703 micrograms per day. In clinical trials, only 3 of 150 patients required daily doses greater than 1000 mcg/ day. Pediatric Patients: Use same dosing recommendations for patients with spasticity of cerebral origin. Pediatric patients under 12 years seemed to require a lower daily dose in clinical trials. Average daily dose for patients under 12 years was 274 mcg/ day, with a range of 24 to 1199 mcg/ day. Dosage requirement for pediatric patients over 12 years does not seem to be different from that of adult patients. Determination of the optimal LIORESAL INTRATHECAL dose requires individual titration. The lowest dose with an optimal response should be used. Potential need for dose adjustments in chronic use : During long term treatment, approximately 5% (28/627) of patients become refractory to increasing doses. There is not sufficient experience to make firm recommendations for tolerance treatment; however, this “tolerance” has been treated on occasion, in hospital, by a “drug holiday” consisting of the gradual reduction of LIORESAL INTRATHECAL over a 2 to 4 week period and switching to alternative methods of spasticity management. After the “drug holiday,” LIORESAL INTRATHECAL may be restarted at the initial continuous infusion dose. Stability Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. Reference ID: 3039097 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Delivery Specifications The specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. LIORESAL INTRATHECAL may require dilution when used with certain implantable pumps. Please consult manufacturer’s manual for specific recommendations. Preparation Instruction: Screening Use the 1 mL screening ampule only (50 mcg/mL) for bolus injection into the subarachnoid space. For a 50mcg bolus dose, use 1 mL of the screening ampule. Use 1.5 mL of 50 mcg/mL baclofen injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg/mL baclofen injection (2 screening ampules). Maintenance For patients who require concentrations other than 500 mcg/mL or 2000 mcg/mL, LIORESAL INTRATHECAL must be diluted. LIORESAL INTRATHECAL must be diluted with sterile preservative free Sodium Chloride for Injection, U.S.P. Delivery Regimen: LIORESAL INTRATHECAL is most often administered in a continuous infusion mode immediately following implant. For those patients implanted with programmable pumps who have achieved relatively satisfactory control on continuous infusion, further benefit may be attained using more complex schedules of LIORESAL INTRATHECAL delivery. For example, patients who have increased spasms at night may require a 20% increase in their hourly infusion rate. Changes in flow rate should be programmed to start two hours before the time of desired clinical effect. HOW SUPPLIED LIORESAL INTRATHECAL (baclofen injection) is available in single use ampules of 10 mg/20 mL (500 mcg/ mL) or 10 mg/ 5 mL (2000 mcg/mL) or 40 mg/20 mL (2000 mcg/mL) packaged in a Refill Kit for intrathecal administration. For screening, LIORESAL INTRATHECAL is available in a single use ampule of 0.05 mg/ 1 mL. Model 8561 LIORESAL INTRATHECAL Refill Kit contains one ampule of 10 mg/ 20 mL (500 mcg/mL) (NDC 58281-560-01). Model 8562 LIORESAL INTRATHECAL Refill Kit contains two ampules of 10 mg/ 5 mL (2000 mcg/mL) (NDC 58281-561-02). Model 8563s LIORESAL INTRATHECAL contains one ampule of 0.05 mg/ 1 mL (NDC 58281-562-01). Model 8564 LIORESAL INTRATHECAL Refill Kit contains four ampules of 10 mg/ 5 mL (2000 mcg/mL) (NDC 58281-561-04) or one ampule of 40 mg/20 mL (2000 mcg/mL) (NDC 58281-563-01). Model 8565 LIORESAL INTRATHECAL Refill Kit contains two ampules of 10 mg/ 20 mL (500 mcg/mL) (NDC 58281-560-02). Model 8566 LIORESAL INTRATHECAL Refill Kit contains eight ampules of 10 mg/ 5 mL (2000 mcg/mL) (NDC 58281-561-08) or two ampules of 40 mg/20 mL (2000 mcg/mL) (NDC 58281-563-02). STORAGE Does not require refrigeration. Do not store above 86° F (30° C). Do not freeze. Do not heat sterilize. Manufactured by Novartis Pharma Stein AG, Stein, Switzerland, for Medtronic, Inc., Minneapolis, Minnesota 55432- 5604 USA. Lioresal® is a registered trademark of Medtronic, Inc. Medtronic, Inc. 710 Medtronic Parkway NE Reference ID: 3039097 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Minneapolis, MN 55432- 5604 USA www.medtronic.com Tel. 763-505-5000 Toll- free 1-800-328-0810 Fax 763-505-1000 Rev. 0811 Reference ID: 3039097 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:40.446466	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020075s024lbl.pdf', 'application_number': 20075, 'submission_type': 'SUPPL ', 'submission_number': 24}
12,182	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DO NOT OPEN POUCH UNTIL READY TO USE. DIRECTIONS: Apply one patch to a dry, clean, hairless portion of upper body or arms. Refer to Self-Help Guide for detailed directions. DO NOT CUT PATCH. KEEP OUT OF REACH OF CHILDREN AND PETS. Used patches have enough nicotine to poison children and pets. If swallowed, get medical help or contact a Poison Control Center right away. Save pouch to use for patch disposal. Dispose of the used patch by folding sticky ends together and putting in pouch. Store at 20-25˚C (68-77˚F). DO NOT USE IF INDIVIDUAL POUCH IS OPEN OR TORN, OR IF PATCH IS CUT. EXP LOT Distributed by: Novartis Consumer Health, Inc. Parsippany, NJ 07054-0622 ©2006 Novartis TO OPEN CUT ALONG DOTTED LINE ✂ 28016F 21mg 21 mg delivered over 24 hours STOP SMOKING AID Nicotine Transdermal System PATCH STEP 1 3 9 0067-5126-09 F.P.O. (b) (4) This label may not be the latest approved by FDA. urrent labeling information, please visit https://www.fda.gov/drugs This label may not be the latest approved by FDA. nt labeling information, please visit https://www.fda.gov/d TO OPEN CUT ALONG DOTTED LINE ✂ 28014F 7mg DO NOT OPEN POUCH UNTIL READY TO USE. DIRECTIONS: Apply one patch to a dry, clean, hairless portion of upper body or arms. Refer to Self-Help Guide for detailed directions. DO NOT CUT PATCH. KEEP OUT OF REACH OF CHILDREN AND PETS. Used patches have enough nicotine to poison children and pets. If swallowed, get medical help or contact a Poison Control Center right away. Save pouch to use for patch disposal. Dispose of the used patch by folding sticky ends together and putting in pouch. Store at 20-25˚C (68-77˚F). DO NOT USE IF INDIVIDUAL POUCH IS OPEN OR TORN, OR IF PATCH IS CUT. 7 mg delivered over 24 hours STOP SMOKING AID Nico e T a sder a Sys e PATCH EXP LOT Distributed by: Novartis Consumer Health, Inc. Parsippany, NJ 07054-0622 ©2006 Novartis STEP 3 3 5 0067-5124-09 F.P.O. (b) (4) This label may not be the latest approved by FDA. abeling information, please visit https://www.fda.gov	custom-source	2025-02-12T13:46:40.614808	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020076Orig1s036lbl.pdf', 'application_number': 20076, 'submission_type': 'SUPPL ', 'submission_number': 36}
12,183	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- THERESA M MICHELE 05/10/2016 Reference ID: 3928951 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:40.652946	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/20076Orig1s041Lbl.pdf', 'application_number': 20076, 'submission_type': 'SUPPL ', 'submission_number': 41}
12,184	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:40.718736	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020076Orig1s042lbl.pdf', 'application_number': 20076, 'submission_type': 'SUPPL ', 'submission_number': 42}
12,185	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- THERESA M MICHELE 07/05/2016 Reference ID: 3954735 (b This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:40.839102	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020076Orig1s043lbl.pdf', 'application_number': 20076, 'submission_type': 'SUPPL ', 'submission_number': 43}
12,186	NDA 20-080/S-036 Package Insert Page 1 of 24 1 PRESCRIBING INFORMATION 1 IMITREX® 2 (sumatriptan succinate) 3 Injection 4 5 For Subcutaneous Use Only. 6 DESCRIPTION 7 IMITREX (sumatriptan succinate) Injection is a selective 5-hydroxytryptamine1 receptor 8 subtype agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]- 9 N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: 10 11 12 13 The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5. 14 Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in 15 saline. 16 IMITREX Injection is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for 17 subcutaneous injection. Each 0.5 mL of IMITREX Injection 8 mg/mL solution contains 4 mg of 18 sumatriptan (base) as the succinate salt and 3.8 mg of sodium chloride, USP in Water for 19 Injection, USP. Each 0.5 mL of IMITREX Injection 12 mg/mL solution contains 6 mg of 20 sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for 21 Injection, USP. The pH range of both solutions is approximately 4.2 to 5.3. The osmolality of 22 both injections is 291 mOsmol. 23 CLINICAL PHARMACOLOGY 24 Mechanism of Action: Sumatriptan has been demonstrated to be a selective agonist for a 25 vascular 5-hydroxytryptamine1 receptor subtype (probably a member of the 5-HT1D family) with 26 no significant affinity (as measured using standard radioligand binding assays) or 27 pharmacological activity at 5-HT2, 5-HT3 receptor subtypes or at alpha1-, alpha2-, or 28 beta-adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors. 29 The vascular 5-HT1 receptor subtype to which sumatriptan binds selectively, and through 30 which it presumably exerts its antimigrainous effect, has been shown to be present on cranial 31 arteries in both dog and primate, on the human basilar artery, and in the vasculature of the 32 isolated dura mater of humans. In these tissues, sumatriptan activates this receptor to cause 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 2 of 24 2 vasoconstriction, an action in humans correlating with the relief of migraine and cluster 34 headache. In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow 35 with little or no effect on arterial blood pressure or total peripheral resistance. In the cat, 36 sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect 37 on blood flow or resistance in cerebral or extracerebral tissues. 38 Corneal Opacities: Dogs receiving oral sumatriptan developed corneal opacities and defects 39 in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 2 mg/kg/day, 40 and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 41 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses 42 were not established; however, the relative exposure at the lowest dose tested was approximately 43 5 times the human exposure after a 100-mg oral dose or 3 times the human exposure after a 6-mg 44 subcutaneous dose. 45 Melanin Binding: In rats with a single subcutaneous dose (0.5 mg/kg) of radiolabeled 46 sumatriptan, the elimination half-life of radioactivity from the eye was 15 days, suggesting that 47 sumatriptan and its metabolites bind to the melanin of the eye. The clinical significance of this 48 binding is unknown. 49 Pharmacokinetics: Pharmacokinetic parameters following a 6-mg subcutaneous injection into 50 the deltoid area of the arm in 9 males (mean age, 33 years; mean weight, 77 kg) were systemic 51 clearance: 1,194 ± 149 mL/min (mean ± S.D.), distribution half-life: 15 ± 2 minutes, terminal 52 half-life: 115 ± 19 minutes, and volume of distribution central compartment: 50 ± 8 liters. Of this 53 dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the indole 54 acetic acid metabolite. 55 After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 56 healthy males (age, 24 ± 6 years; weight, 70 kg), the maximum serum concentration (Cmax) was 57 (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (Tmax) was 58 12 minutes after injection (range, 5 to 20 minutes). In this study, the same dose injected 59 subcutaneously in the thigh gave a Cmax of 61 ± 15 ng/mL by manual injection versus 60 52 ± 15 ng/mL by autoinjector techniques. The Tmax or amount absorbed was not significantly 61 altered by either the site or technique of injection. 62 The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects 63 was 97% ± 16% of that obtained following intravenous injection. Protein binding, determined by 64 equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL, is low, approximately 65 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been 66 evaluated. 67 Special Populations: Renal Impairment: The effect of renal impairment on the 68 pharmacokinetics of sumatriptan has not been examined, but little clinical effect would be 69 expected as sumatriptan is largely metabolized to an inactive substance. 70 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 3 of 24 3 Hepatic Impairment: The effect of hepatic disease on the pharmacokinetics of 71 subcutaneously and orally administered sumatriptan has been evaluated. There were no 72 statistically significant differences in the pharmacokinetics of subcutaneously administered 73 sumatriptan in hepatically impaired patients compared to healthy controls. However, the liver 74 plays an important role in the presystemic clearance of orally administered sumatriptan. 75 Accordingly, the bioavailability of sumatriptan following oral administration may be markedly 76 increased in patients with liver disease. In 1 small study of hepatically impaired patients (n = 8) 77 matched for sex, age, and weight with healthy subjects, the hepatically impaired patients had an 78 approximately 70% increase in AUC and Cmax and a Tmax 40 minutes earlier compared to the 79 healthy subjects. 80 Age: The pharmacokinetics of sumatriptan in the elderly (mean age, 72 years, 2 males and 81 4 females) and in patients with migraine (mean age, 38 years, 25 males and 155 females) were 82 similar to that in healthy male subjects (mean age, 30 years) (see PRECAUTIONS: Geriatric 83 Use). 84 Race: The systemic clearance and Cmax of sumatriptan were similar in black (N = 34) and 85 Caucasian (N = 38) healthy male subjects. 86 Drug Interactions: Monoamine Oxidase Inhibitors: In vitro studies with human 87 microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), 88 predominantly the A isoenzyme. In a study of 14 healthy females, pretreatment with MAO-A 89 inhibitor decreased the clearance of sumatriptan. Under the conditions of this experiment, the 90 result was a 2-fold increase in the area under the sumatriptan plasma concentration x time curve 91 (AUC), corresponding to a 40% increase in elimination half-life. No significant effect was seen 92 with an MAO-B inhibitor. 93 Pharmacodynamics: 94 Typical Physiologic Responses: 95 Blood Pressure: (see WARNINGS: Increase in Blood Pressure) 96 Peripheral (small) Arteries: In healthy volunteers (N = 18), a study evaluating the effects 97 of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically 98 significant increase in peripheral resistance. 99 Heart Rate: Transient increases in blood pressure observed in some patients in clinical 100 studies carried out during sumatriptan’s development as a treatment for migraine were not 101 accompanied by any clinically significant changes in heart rate. 102 Respiratory Rate: Experience gained during the clinical development of sumatriptan as a 103 treatment for migraine failed to detect an effect of the drug on respiratory rate. 104 CLINICAL TRIALS 105 Migraine: In US controlled clinical trials enrolling more than 1,000 patients during migraine 106 attacks who were experiencing moderate or severe pain and 1 or more of the symptoms 107 enumerated in Table 2, onset of relief began as early as 10 minutes following a 6-mg IMITREX 108 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 4 of 24 4 Injection. Smaller doses of sumatriptan may also prove effective, although the proportion of 109 patients obtaining adequate relief is decreased and the latency to that relief is greater. 110 In 1 well-controlled study where placebo (n = 62) was compared to 6 different doses of 111 IMITREX Injection (n = 30 each group) in a single-attack, parallel-group design, the dose 112 response relationship was found to be as shown in Table 1. 113 114 Table 1. Dose Response Relationship for Efficacy 115 IMITREX Dose (mg) % Patients With Relief* at 10 Minutes % Patients With Relief* at 30 Minutes % Patients With Relief* at 1 Hour % Patients With Relief* at 2 Hours Adverse Events Incidence (%) Placebo 1 2 3 4 6 8 5 10 7 17 13 10 23 15 40 23 47 37 63 57 24 43 57 57 50 73 80 21 40 43 60 57 70 83 55 63 63 77 80 83 93 * Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication. 116 In 2 US well-controlled clinical trials in 1,104 migraine patients with moderate or severe 117 migraine pain, the onset of relief was rapid (less than 10 minutes) with IMITREX Injection 6 mg. 118 Headache relief, as evidenced by a reduction in pain from severe or moderately severe to mild or 119 no headache, was achieved in 70% of the patients within 1 hour of a single 6-mg subcutaneous 120 dose of IMITREX Injection. Headache relief was achieved in approximately 82% of patients 121 within 2 hours, and 65% of all patients were pain free within 2 hours. 122 Table 2 shows the 1- and 2-hour efficacy results for IMITREX Injection 6 mg. 123 124 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 5 of 24 5 Table 2. Efficacy Data From US Phase III Trials 125 Study 1 Study 2 1-Hour Data Placebo (n = 190) IMITREX 6 mg (n = 384) Placebo (n = 180) IMITREX 6 mg (n = 350) Patients with pain relief (grade 0/1) 18% 70%* 26% 70%* Patients with no pain 5% 48%* 13% 49%* Patients without nausea 48% 73%* 50% 73%* Patients without photophobia 23% 56%* 25% 58%* Patients with little or no clinical disability§ 34% 76%* 34% 76%* Study 1 Study 2 2-Hour Data Placebo† IMITREX 6 mg‡ Placebo† IMITREX 6 mg‡ Patients with pain relief (grade 0/1) 31% 81%* 39% 82%* Patients with no pain 11% 63%* 19% 65%* Patients without nausea 56% 82%* 63% 81%* Patients without photophobia 31% 72%* 35% 71%* Patients with little or no clinical disability§ 42% 85%* 49% 84%* * p<0.05 versus placebo. † Includes patients that may have received an additional placebo injection 1 hour after the initial injection. ‡ Includes patients that may have received an additional 6 mg of IMITREX Injection 1 hour after the initial injection. § A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. 126 IMITREX Injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and 127 vomiting associated with migraine attacks. Similar efficacy was seen when patients 128 self-administered IMITREX Injection using an autoinjector. 129 The efficacy of IMITREX Injection is unaffected by whether or not migraine is associated 130 with aura, duration of attack, gender or age of the patient, or concomitant use of common 131 migraine prophylactic drugs (e.g., beta-blockers). 132 Cluster Headache: The efficacy of IMITREX Injection in the acute treatment of cluster 133 headache was demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period 134 crossover trials. Patients age 21 to 65 were enrolled and were instructed to treat a moderate to 135 very severe headache within 10 minutes of onset. Headache relief was defined as a reduction in 136 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 6 of 24 6 headache severity to mild or no pain. In both trials, the proportion of individuals gaining relief at 137 10 or 15 minutes was significantly greater among patients receiving 6 mg of IMITREX Injection 138 compared to those who received placebo (see Table 3). One study evaluated a 12-mg dose; there 139 was no statistically significant difference in outcome between patients randomized to the 6- and 140 12-mg doses. 141 142 Table 3. Efficacy Data From the Pivotal Cluster Headache Studies 143 Study 1 Study 2 Placebo (n = 39) IMITREX 6 mg (n = 39) Placebo (n = 88) IMITREX 6 mg (n = 92) Patients with pain relief (no/mild) 5 minutes postinjection 8% 21% 7% 23%* 10 minutes postinjection 10% 49%* 25% 49%* 15 minutes postinjection 26% 74%* 35% 75%* p<0.05. (n = Number of headaches treated.) 144 The Kaplan-Meier (product limit) Survivorship Plot (Figure 1) provides an estimate of the 145 cumulative probability of a patient with a cluster headache obtaining relief after being treated 146 with either sumatriptan or placebo. 147 148 Figure 1. Time to Relief From Time of Injection 149 150 151 Patients taking rescue medication were censored at 15 minutes. 152 153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 7 of 24 7 The plot was constructed with data from patients who either experienced relief or did not 154 require (request) rescue medication within a period of 2 hours following treatment. As a 155 consequence, the data in the plot are derived from only a subset of the 258 headaches treated 156 (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 157 sumatriptan-treated headaches). 158 Other data suggest that sumatriptan treatment is not associated with an increase in early 159 recurrence of headache, and that treatment with sumatriptan has little effect on the incidence of 160 latter-occurring headaches (i.e., those occurring after 2, but before 18 or 24 hours). 161 INDICATIONS AND USAGE 162 IMITREX Injection is indicated for 1) the acute treatment of migraine attacks with or without 163 aura and 2) the acute treatment of cluster headache episodes. 164 IMITREX Injection is not for use in the management of hemiplegic or basilar migraine (see 165 CONTRAINDICATIONS). 166 CONTRAINDICATIONS 167 IMITREX Injection should not be given intravenously because of its potential to cause 168 coronary vasospasm. 169 IMITREX Injection should not be given to patients with history, symptoms, or signs of 170 ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. In addition, patients 171 with other significant underlying cardiovascular diseases should not receive IMITREX 172 Injection. Ischemic cardiac syndromes include, but are not limited to, angina pectoris of 173 any type (e.g., stable angina of effort and vasospastic forms of angina such as the 174 Prinzmetal variant), all forms of myocardial infarction, and silent myocardial ischemia. 175 Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as 176 transient ischemic attacks. Peripheral vascular disease includes, but is not limited to, 177 ischemic bowel disease (see WARNINGS: Other Vasospasm-Related Events and 178 WARNINGS: Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac 179 Events). 180 Because IMITREX Injection may increase blood pressure, it should not be given to 181 patients with uncontrolled hypertension. 182 IMITREX Injection and any ergotamine-containing or ergot-type medication (like 183 dihydroergotamine or methysergide) should not be used within 24 hours of each other, nor 184 should IMITREX Injection and another 5-HT1 agonist. 185 IMITREX Injection should not be administered to patients with hemiplegic or basilar 186 migraine. 187 IMITREX Injection is contraindicated in patients with hypersensitivity to sumatriptan 188 or any of its components. 189 IMITREX Injection is contraindicated in patients with severe hepatic impairment. 190 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 8 of 24 8 WARNINGS 191 IMITREX Injection should only be used where a clear diagnosis of migraine or cluster 192 headache has been established. The prescriber should be aware that cluster headache 193 patients often possess one or more predictive risk factors for coronary artery disease 194 (CAD). 195 Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: 196 Sumatriptan should not be given to patients with documented ischemic or vasospastic CAD 197 (see CONTRAINDICATIONS). It is strongly recommended that sumatriptan not be given 198 to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., 199 hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of 200 CAD, female with surgical or physiological menopause, or male over 40 years of age) unless 201 a cardiovascular evaluation provides satisfactory clinical evidence that the patient is 202 reasonably free of coronary artery and ischemic myocardial disease or other significant 203 underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to 204 detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at 205 best. If, during the cardiovascular evaluation, the patient’s medical history or 206 electrocardiographic investigations reveal findings indicative of or consistent with coronary 207 artery vasospasm or myocardial ischemia, sumatriptan should not be administered (see 208 CONTRAINDICATIONS). 209 For patients with risk factors predictive of CAD who are determined to have a 210 satisfactory cardiovascular evaluation, it is strongly recommended that administration of 211 the first dose of sumatriptan injection take place in the setting of a physician’s office or 212 similar medically staffed and equipped facility. Because cardiac ischemia can occur in the 213 absence of clinical symptoms, consideration should be given to obtaining on the first 214 occasion of use an electrocardiogram (ECG) during the interval immediately following 215 IMITREX Injection, in these patients with risk factors. 216 It is recommended that patients who are intermittent long-term users of sumatriptan 217 and who have or acquire risk factors predictive of CAD, as described above, undergo 218 periodic interval cardiovascular evaluation as they continue to use sumatriptan. In 219 considering this recommendation for periodic cardiovascular evaluation, it is noted that 220 patients with cluster headache are predominantly male and over 40 years of age, which are 221 risk factors for CAD. 222 The systematic approach described above is intended to reduce the likelihood that patients 223 with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan. 224 Drug-Associated Cardiac Events and Fatalities: Serious adverse cardiac events, 225 including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death 226 have been reported within a few hours following the administration of IMITREX Injection or 227 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 9 of 24 9 IMITREX® (sumatriptan succinate) Tablets. Considering the extent of use of sumatriptan in 228 patients with migraine, the incidence of these events is extremely low. 229 The fact that sumatriptan can cause coronary vasospasm, that some of these events have 230 occurred in patients with no prior cardiac disease history and with documented absence of CAD, 231 and the close proximity of the events to sumatriptan use support the conclusion that some of 232 these cases were caused by the drug. In many cases, however, where there has been known 233 underlying CAD, the relationship is uncertain. 234 Premarketing Experience With Sumatriptan: Among the more than 1,900 patients with 235 migraine who participated in premarketing controlled clinical trials of subcutaneous sumatriptan, 236 there were 8 patients who sustained clinical events during or shortly after receiving sumatriptan 237 that may have reflected coronary artery vasospasm. Six of these 8 patients had ECG changes 238 consistent with transient ischemia, but without accompanying clinical symptoms or signs. Of 239 these 8 patients, 4 had either findings suggestive of CAD or risk factors predictive of CAD prior 240 to study enrollment. 241 Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled 242 clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving 243 oral sumatriptan that may have reflected coronary vasospasm. Neither of these adverse events 244 was associated with a serious clinical outcome. 245 Among approximately 4,000 patients with migraine who participated in premarketing 246 controlled and uncontrolled clinical trials of sumatriptan nasal spray, 1 patient experienced an 247 asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event. 248 Postmarketing Experience With Sumatriptan: Serious cardiovascular events, some 249 resulting in death, have been reported in association with the use of IMITREX Injection or 250 IMITREX Tablets. The uncontrolled nature of postmarketing surveillance, however, makes it 251 impossible to determine definitively the proportion of the reported cases that were actually 252 caused by sumatriptan or to reliably assess causation in individual cases. On clinical grounds, the 253 longer the latency between the administration of IMITREX and the onset of the clinical event, 254 the less likely the association is to be causative. Accordingly, interest has focused on events 255 beginning within 1 hour of the administration of IMITREX. 256 Cardiac events that have been observed to have onset within 1 hour of sumatriptan 257 administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, 258 ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death. 259 Some of these events occurred in patients who had no findings of CAD and appear to 260 represent consequences of coronary artery vasospasm. However, among domestic reports of 261 serious cardiac events within 1 hour of sumatriptan administration, the majority had risk factors 262 predictive of CAD and the presence of significant underlying CAD was established in most cases 263 (see CONTRAINDICATIONS). 264 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 10 of 24 10 Drug-Associated Cerebrovascular Events and Fatalities: Cerebral hemorrhage, 265 subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in 266 patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The 267 relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible 268 that the cerebrovascular events were primary, sumatriptan having been administered in the 269 incorrect belief the symptoms experienced were a consequence of migraine when they were not. 270 As with other acute migraine therapies, before treating headaches in patients not previously 271 diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should 272 be taken to exclude other potentially serious neurological conditions. It should also be noted that 273 patients with migraine may be at increased risk of certain cerebrovascular events (e.g., 274 cerebrovascular accident, transient ischemic attack). 275 Other Vasospasm-Related Events: Sumatriptan may cause vasospastic reactions other than 276 coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with 277 abdominal pain and bloody diarrhea have been reported. Very rare reports of transient and 278 permanent blindness and significant partial vision loss have been reported with the use of 279 sumatriptan. Visual disorders may also be part of a migraine attack. 280 Increase in Blood Pressure: Significant elevation in blood pressure, including hypertensive 281 crisis, has been reported on rare occasions in patients with and without a history of hypertension. 282 Sumatriptan is contraindicated in patients with uncontrolled hypertension (see 283 CONTRAINDICATIONS). Sumatriptan should be administered with caution to patients with 284 controlled hypertension as transient increases in blood pressure and peripheral vascular resistance 285 have been observed in a small proportion of patients. 286 Concomitant Drug Use: In patients taking MAO-A inhibitors, sumatriptan plasma levels 287 attained after treatment with recommended doses are nearly double those obtained under other 288 conditions. Accordingly, the coadministration of sumatriptan and an MAO-A inhibitor is not 289 generally recommended. If such therapy is clinically warranted, however, suitable dose 290 adjustment and appropriate observation of the patient is advised (see CLINICAL 291 PHARMACOLOGY: Drug Interactions: Monoamine Oxidase Inhibitors). 292 Use in Women of Childbearing Potential: (see PRECAUTIONS: Pregnancy) 293 Hypersensitivity: Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on 294 rare occasions in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In 295 general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history 296 of sensitivity to multiple allergens (see CONTRAINDICATIONS). 297 PRECAUTIONS 298 General: Chest, jaw, or neck tightness is relatively common after administration of IMITREX 299 Injection. Chest discomfort and jaw or neck tightness have been reported following use of 300 IMITREX Tablets and have also been reported infrequently following the administration of 301 IMITREX® (sumatriptan) Nasal Spray. Only rarely have these symptoms been associated with 302 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 11 of 24 11 ischemic ECG changes. However, because sumatriptan may cause coronary artery vasospasm, 303 patients who experience signs or symptoms suggestive of angina following sumatriptan should be 304 evaluated for the presence of CAD or a predisposition to Prinzmetal variant angina before 305 receiving additional doses of sumatriptan and should be monitored electrocardiographically if 306 dosing is resumed and similar symptoms recur. Similarly, patients who experience other 307 symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or 308 Raynaud syndrome, following sumatriptan should be evaluated for atherosclerosis or 309 predisposition to vasospasm (see WARNINGS: Risk of Myocardial Ischemia and/or Infarction 310 and Other Adverse Cardiac Events and WARNINGS: Other Vasospasm-Related Events). 311 IMITREX should also be administered with caution to patients with diseases that may alter the 312 absorption, metabolism, or excretion of drugs, such as impaired hepatic or renal function. 313 There have been rare reports of seizure following administration of sumatriptan. Sumatriptan 314 should be used with caution in patients with a history of epilepsy or conditions associated with a 315 lowered seizure threshold. 316 Care should be taken to exclude other potentially serious neurologic conditions before treating 317 headache in patients not previously diagnosed with migraine or cluster headache or who 318 experience a headache that is atypical for them. There have been rare reports where patients 319 received sumatriptan for severe headaches that were subsequently shown to have been secondary 320 to an evolving neurologic lesion (see WARNINGS: Drug-Associated Cerebrovascular Events 321 and Fatalities). For a given attack, if a patient does not respond to the first dose of sumatriptan, 322 the diagnosis of migraine or cluster headache should be reconsidered before administration of a 323 second dose. 324 Binding to Melanin-Containing Tissues: Because sumatriptan binds to melanin, it could 325 accumulate in melanin-rich tissues (such as the eye) over time. This raises the possibility that 326 sumatriptan could cause toxicity in these tissues after extended use. However, no effects on the 327 retina related to treatment with sumatriptan were noted in any of the toxicity studies. Although no 328 systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no 329 specific recommendations for ophthalmologic monitoring are offered, prescribers should be 330 aware of the possibility of long-term ophthalmologic effects (see CLINICAL 331 PHARMACOLOGY: Melanin Binding). 332 Corneal Opacities: Sumatriptan causes corneal opacities and defects in the corneal epithelium 333 in dogs; this raises the possibility that these changes may occur in humans. While patients were 334 not systematically evaluated for these changes in clinical trials, and no specific recommendations 335 for monitoring are being offered, prescribers should be aware of the possibility of these changes 336 (see CLINICAL PHARMACOLOGY: Corneal Opacities). 337 Patients who are advised to self-administer IMITREX Injection in medically 338 unsupervised situations should receive instruction on the proper use of the product from 339 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 12 of 24 12 the physician or other suitably qualified health care professional prior to doing so for the 340 first time. 341 Information for Patients: With the autoinjector, the needle penetrates approximately 1/4 of an 342 inch (5 to 6 mm). Since the injection is intended to be given subcutaneously, intramuscular or 343 intravascular delivery should be avoided. Patients should be directed to use injection sites with an 344 adequate skin and subcutaneous thickness to accommodate the length of the needle. See 345 PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided 346 for patients. 347 Laboratory Tests: No specific laboratory tests are recommended for monitoring patients prior 348 to and/or after treatment with sumatriptan. 349 Drug Interactions: There is no evidence that concomitant use of migraine prophylactic 350 medications has any effect on the efficacy of sumatriptan. In 2 Phase III trials in the US, a 351 retrospective analysis of 282 patients who had been using prophylactic drugs (verapamil n = 63, 352 amitriptyline n = 57, propranolol n = 94, for 45 other drugs n = 123) were compared to those who 353 had not used prophylaxis (N = 452). There were no differences in relief rates at 60 minutes 354 postdose for IMITREX Injection, whether or not prophylactic medications were used. 355 Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because 356 there is a theoretical basis that these effects may be additive, use of ergotamine-containing or 357 ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 358 24 hours of each other should be avoided (see CONTRAINDICATIONS). 359 MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. 360 Therefore, the use of sumatriptan in patients receiving MAO-A inhibitors is not ordinarily 361 recommended. If the clinical situation warrants the combined use of sumatriptan and an MAOI, 362 the dose of sumatriptan employed should be reduced (see CLINICAL PHARMACOLOGY: Drug 363 Interactions: Monoamine Oxidase Inhibitors and WARNINGS: Concomitant Drug Use). 364 Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, 365 sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when 366 coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is 367 clinically warranted, appropriate observation of the patient is advised. 368 Drug/Laboratory Test Interactions: IMITREX is not known to interfere with commonly 369 employed clinical laboratory tests. 370 Carcinogenesis, Mutagenesis, Impairment of Fertility: In carcinogenicity studies, rats 371 and mice were given sumatriptan by oral gavage (rats, 104 weeks) or drinking water (mice, 372 78 weeks). Average exposures achieved in mice receiving the highest dose were approximately 373 110 times the exposure attained in humans after the maximum recommended single dose of 374 6 mg. The highest dose to rats was approximately 260 times the maximum single dose of 6 mg on 375 a mg/m2 basis. There was no evidence of an increase in tumors in either species related to 376 sumatriptan administration. 377 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 13 of 24 13 Sumatriptan was not mutagenic in the presence or absence of metabolic activation when tested 378 in 2 gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster 379 V79/HGPRT assay). In 2 cytogenetics assays (the in vitro human lymphocyte assay and the in 380 vivo rat micronucleus assay) sumatriptan was not associated with clastogenic activity. 381 A fertility study (Segment I) by the subcutaneous route, during which male and female rats 382 were dosed daily with sumatriptan prior to and throughout the mating period, has shown no 383 evidence of impaired fertility at doses equivalent to approximately 100 times the maximum 384 recommended single human dose of 6 mg on a mg/m2 basis. However, following oral 385 administration, a treatment-related decrease in fertility, secondary to a decrease in mating, was 386 seen for rats treated with 50 and 500 mg/kg/day. The no-effect dose for this finding was 387 approximately 8 times the maximum recommended single human dose of 6 mg on a mg/m2 basis. 388 It is not clear whether the problem is associated with the treatment of males or females or both. 389 Pregnancy: Pregnancy Category C. Sumatriptan has been shown to be embryolethal in rabbits 390 when given daily at a dose approximately equivalent to the maximum recommended single 391 human subcutaneous dose of 6 mg on a mg/m2 basis. There is no evidence that establishes that 392 sumatriptan is a human teratogen; however, there are no adequate and well-controlled studies in 393 pregnant women. IMITREX Injection should be used during pregnancy only if the potential 394 benefit justifies the potential risk to the fetus. 395 In assessing this information, the following additional findings should be considered. 396 Embryolethality: When given intravenously to pregnant rabbits daily throughout the period 397 of organogenesis, sumatriptan caused embryolethality at doses at or close to those producing 398 maternal toxicity. The mechanism of the embryolethality is not known. These doses were 399 approximately equivalent to the maximum single human dose of 6 mg on a mg/m2 basis. 400 The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at 401 doses that are approximately 20 times a human dose of 6 mg on a mg/m2 basis, did not cause 402 embryolethality. Additionally, in a study of pregnant rats given subcutaneous sumatriptan daily 403 prior to and throughout pregnancy, there was no evidence of increased embryo/fetal lethality. 404 Teratogenicity: Term fetuses from Dutch Stride rabbits treated during organogenesis with 405 oral sumatriptan exhibited an increased incidence of cervicothoracic vascular and skeletal 406 abnormalities. The functional significance of these abnormalities is not known. The highest 407 no-effect dose for these effects was 15 mg/kg/day, approximately 50 times the maximum single 408 dose of 6 mg on a mg/m2 basis. 409 In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout 410 pregnancy, there was no evidence of teratogenicity. 411 Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to IMITREX, 412 GlaxoSmithKline maintains a Sumatriptan Pregnancy Registry. Physicians are encouraged to 413 register patients by calling (800) 336-2176. 414 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 14 of 24 14 Nursing Mothers: Sumatriptan is excreted in human breast milk. Therefore, caution should be 415 exercised when considering the administration of IMITREX Injection to a nursing woman. 416 Pediatric Use: Safety and effectiveness of IMITREX Injection in pediatric patients under 18 417 years of age have not been established; therefore, IMITREX Injection is not recommended for 418 use in patients under 18 years of age. 419 Two controlled clinical trials evaluating sumatriptan nasal spray (5 to 20 mg) in pediatric 420 patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single 421 attack. The studies did not establish the efficacy of sumatriptan nasal spray compared to placebo 422 in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were 423 similar in nature to those reported in clinical trials in adults. 424 Five controlled clinical trials (2 single-attack studies, 3 multiple-attack studies) evaluating oral 425 sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 426 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared 427 to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical 428 trials were similar in nature to those reported in clinical trials in adults. The frequency of all 429 adverse events in these patients appeared to be both dose- and age-dependent, with younger 430 patients reporting events more commonly than older adolescents. 431 Postmarketing experience documents that serious adverse events have occurred in the 432 pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports 433 include events similar in nature to those reported rarely in adults, including stroke, visual loss, 434 and death. A myocardial infarction has been reported in a 14-year-old male following the use of 435 oral sumatriptan; clinical signs occurred within 1 day of drug administration. Since clinical data 436 to determine the frequency of serious adverse events in pediatric patients who might receive 437 injectable, oral, or intranasal sumatriptan are not presently available, the use of sumatriptan in 438 patients aged younger than 18 years is not recommended. 439 Geriatric Use: The use of sumatriptan in elderly patients is not recommended because elderly 440 patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and 441 blood pressure increases may be more pronounced in the elderly (see WARNINGS: Risk of 442 Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events). 443 ADVERSE REACTIONS 444 Serious cardiac events, including some that have been fatal, have occurred following the 445 use of IMITREX Injection or Tablets. These events are extremely rare and most have been 446 reported in patients with risk factors predictive of CAD. Events reported have included 447 coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, 448 ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, 449 WARNINGS: Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events, 450 and PRECAUTIONS: General). 451 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 15 of 24 15 Significant hypertensive episodes, including hypertensive crises, have been reported on rare 452 occasions in patients with or without a history of hypertension (see WARNINGS: Increase in 453 Blood Pressure). 454 Among patients in clinical trials of subcutaneous IMITREX Injection (N = 6,218), up to 3.5% 455 of patients withdrew for reasons related to adverse events. 456 Incidence in Controlled Clinical Trials of Migraine Headache: Table 4 lists adverse 457 events that occurred in 2 large US, Phase III, placebo-controlled clinical trials in migraine 458 patients following either a single 6-mg dose of IMITREX Injection or placebo. Only events that 459 occurred at a frequency of 2% or more in groups treated with IMITREX Injection 6 mg and 460 occurred at a frequency greater than the placebo group are included in Table 4. 461 462 Table 4. Treatment-Emergent Adverse Experience Incidence in 2 Large 463 Placebo-Controlled Migraine Clinical Trials: Events Reported by at Least 2% of 464 Patients Treated With IMITREX Injection 6 mg 465 Percent of Patients Reporting Adverse Event IMITREX Injection 6 mg Subcutaneous (n = 547) Placebo (n = 370) Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort 5 1 Tightness in chest 3 <1 Pressure in chest 2 <1 Ear, nose, and throat Throat discomfort 3 <1 Discomfort: nasal cavity/sinuses 2 <1 Injection site reaction 59 24 Miscellaneous This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 16 of 24 16 Jaw discomfort 2 0 Musculoskeletal Weakness 5 <1 Neck pain/stiffness 5 <1 Myalgia 2 <1 Neurological Dizziness/vertigo 12 4 Drowsiness/sedation 3 2 Headache 2 <1 Skin Sweating 2 1 *The sum of the percentages cited is greater than 100% because patients may experience more than 1 type of adverse event. Only events that occurred at a frequency of 2% or more in groups treated with IMITREX Injection and occurred at a frequency greater than the placebo groups are included. 466 The incidence of adverse events in controlled clinical trials was not affected by gender or age 467 of the patients. There were insufficient data to assess the impact of race on the incidence of 468 adverse events. 469 Incidence in Controlled Trials of Cluster Headache: In the controlled clinical trials 470 assessing sumatriptan’s efficacy as a treatment for cluster headache, no new significant adverse 471 events associated with the use of sumatriptan were detected that had not already been identified 472 in association with the drug’s use in migraine. 473 Overall, the frequency of adverse events reported in the studies of cluster headache were 474 generally lower. Exceptions include reports of paresthesia (5% IMITREX, 0% placebo), nausea 475 and vomiting (4% IMITREX, 0% placebo), and bronchospasm (1% IMITREX, 0% placebo). 476 Other Events Observed in Association With the Administration of IMITREX 477 Injection: In the paragraphs that follow, the frequencies of less commonly reported adverse 478 clinical events are presented. Because the reports include events observed in open and 479 uncontrolled studies, the role of IMITREX Injection in their causation cannot be reliably 480 determined. Furthermore, variability associated with adverse event reporting, the terminology 481 used to describe adverse events, etc., limit the value of the quantitative frequency estimates 482 provided. 483 Event frequencies are calculated as the number of patients reporting an event divided by the 484 total number of patients (N = 6,218) exposed to subcutaneous IMITREX Injection. All reported 485 events are included except those already listed in the previous table, those too general to be 486 informative, and those not reasonably associated with the use of the drug. Events are further 487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 17 of 24 17 classified within body system categories and enumerated in order of decreasing frequency using 488 the following definitions: frequent adverse events are defined as those occurring in at least 1/100 489 patients, infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, and rare 490 adverse events are those occurring in fewer than 1/1,000 patients. 491 Cardiovascular: Infrequent were hypertension, hypotension, bradycardia, tachycardia, 492 palpitations, pulsating sensations, various transient ECG changes (nonspecific ST or T wave 493 changes, prolongation of PR or QTc intervals, sinus arrhythmia, nonsustained ventricular 494 premature beats, isolated junctional ectopic beats, atrial ectopic beats, delayed activation of the 495 right ventricle), and syncope. Rare were pallor, arrhythmia, abnormal pulse, vasodilatation, and 496 Raynaud syndrome. 497 Endocrine and Metabolic: Infrequent was thirst. Rare were polydipsia and dehydration. 498 Eye: Frequent was vision alterations. Infrequent was irritation of the eye. 499 Gastrointestinal: Frequent were abdominal discomfort and dysphagia. Infrequent were 500 gastroesophageal reflux and diarrhea. Rare were peptic ulcer, retching, flatulence/eructation, and 501 gallstones. 502 Musculoskeletal: Frequent were muscle cramps. Infrequent were various joint disturbances 503 (pain, stiffness, swelling, ache). Rare were muscle stiffness, need to flex calf muscles, backache, 504 muscle tiredness, and swelling of the extremities. 505 Neurological: Frequent was anxiety. Infrequent were mental confusion, euphoria, agitation, 506 relaxation, chills, sensation of lightness, tremor, shivering, disturbances of taste, prickling 507 sensations, paresthesia, stinging sensations, facial pain, photophobia, and lacrimation. Rare were 508 transient hemiplegia, hysteria, globus hystericus, intoxication, depression, myoclonia, 509 monoplegia/diplegia, sleep disturbance, difficulties in concentration, disturbances of smell, 510 hyperesthesia, dysesthesia, simultaneous hot and cold sensations, tickling sensations, dysarthria, 511 yawning, reduced appetite, hunger, and dystonia. 512 Respiratory: Infrequent was dyspnea. Rare were influenza, diseases of the lower respiratory 513 tract, and hiccoughs. 514 Skin: Infrequent were erythema, pruritus, and skin rashes and eruptions. Rare was skin 515 tenderness. 516 Urogenital: Rare were dysuria, frequency, dysmenorrhea, and renal calculus. 517 Miscellaneous: Infrequent were miscellaneous laboratory abnormalities, including minor 518 disturbances in liver function tests, “serotonin agonist effect,” and hypersensitivity to various 519 agents. Rare was fever. 520 Other Events Observed in the Clinical Development of IMITREX: The following 521 adverse events occurred in clinical trials with IMITREX Tablets and IMITREX Nasal Spray. 522 Because the reports include events observed in open and uncontrolled studies, the role of 523 IMITREX in their causation cannot be reliably determined. All reported events are included 524 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 18 of 24 18 except those already listed, those too general to be informative, and those not reasonably 525 associated with the use of the drug. 526 Breasts: Breast swelling, cysts, disorder of breasts, lumps, masses of breasts, nipple 527 discharge, primary malignant breast neoplasm, and tenderness. 528 Cardiovascular: Abdominal aortic aneurysm, angina, atherosclerosis, cerebral ischemia, 529 cerebrovascular lesion, heart block, peripheral cyanosis, phlebitis, thrombosis, and transient 530 myocardial ischemia. 531 Ear, Nose, and Throat: Allergic rhinitis; disorder of nasal cavity/sinuses; ear, nose, and 532 throat hemorrhage; ear infection; external otitis; feeling of fullness in the ear(s); hearing 533 disturbances; hearing loss; Meniere disease; nasal inflammation; otalgia; sensitivity to noise; 534 sinusitis; tinnitus; and upper respiratory inflammation. 535 Endocrine and Metabolic: Elevated thyrotropin stimulating hormone (TSH) levels; 536 endocrine cysts, lumps, and masses; fluid disturbances; galactorrhea; hyperglycemia; 537 hypoglycemia; hypothyroidism; weight gain; and weight loss. 538 Eye: Accommodation disorders, blindness and low vision, conjunctivitis, disorders of sclera, 539 external ocular muscle disorders, eye edema and swelling, eye hemorrhage, eye itching, eye pain, 540 keratitis, mydriasis, and visual disturbances. 541 Gastrointestinal: Abdominal distention, colitis, constipation, dental pain, dyspeptic 542 symptoms, feelings of gastrointestinal pressure, gastric symptoms, gastritis, gastroenteritis, 543 gastrointestinal bleeding, gastrointestinal pain, hematemesis, hypersalivation, hyposalivation, 544 intestinal obstruction, melena, nausea and/or vomiting, oral itching and irritation, pancreatitis, 545 salivary gland swelling, and swallowing disorders. 546 Hematological Disorders: Anemia. 547 Mouth and Teeth: Disorder of mouth and tongue (e.g., burning of tongue, numbness of 548 tongue, dry mouth). 549 Musculoskeletal: Acquired musculoskeletal deformity, arthralgia and articular rheumatitis, 550 arthritis, intervertebral disc disorder, muscle atrophy, muscle tightness and rigidity, 551 musculoskeletal inflammation, and tetany. 552 Neurological: Apathy, aggressiveness, bad/unusual taste, bradylogia, cluster headache, 553 convulsions, depressive disorders, detachment, disturbance of emotions, drug abuse, facial 554 paralysis, hallucinations, heat sensitivity, incoordination, increased alertness, memory 555 disturbance, migraine, motor dysfunction, neoplasm of pituitary, neuralgia, neurotic disorders, 556 paralysis, personality change, phobia, phonophobia, psychomotor disorders, radiculopathy, 557 raised intracranial pressure, rigidity, stress, syncope, suicide, and twitching. 558 Respiratory: Asthma, breathing disorders, bronchitis, cough, and lower respiratory tract 559 infection. 560 Skin: Dry/scaly skin, eczema, herpes, seborrheic dermatitis, skin nodules, tightness of skin, 561 and wrinkling of skin. 562 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 19 of 24 19 Urogenital: Abnormal menstrual cycle, abortion, bladder inflammation, endometriosis, 563 hematuria, increased urination, inflammation of fallopian tubes, intermenstrual bleeding, 564 menstruation symptoms, micturition disorders, urethritis, and urinary infections. 565 Miscellaneous: Contusions, difficulty in walking, edema, hematoma, hypersensitivity, 566 fever, fluid retention, lymphadenopathy, overdose, speech disturbance, swelling of extremities, 567 swelling of face, and voice disturbances. 568 Pain and Other Pressure Sensations: Chest pain and/or heaviness, neck/throat/jaw 569 pain/tightness/pressure, and pain (location specified). 570 Postmarketing Experience (Reports for Subcutaneous or Oral Sumatriptan): The 571 following section enumerates potentially important adverse events that have occurred in clinical 572 practice and that have been reported spontaneously to various surveillance systems. The events 573 enumerated represent reports arising from both domestic and nondomestic use of oral or 574 subcutaneous dosage forms of sumatriptan. The events enumerated include all except those 575 already listed in the ADVERSE REACTIONS section above or those too general to be 576 informative. Because the reports cite events reported spontaneously from worldwide 577 postmarketing experience, frequency of events and the role of IMITREX Injection in their 578 causation cannot be reliably determined. It is assumed, however, that systemic reactions 579 following sumatriptan use are likely to be similar regardless of route of administration. 580 Blood: Hemolytic anemia, pancytopenia, thrombocytopenia. 581 Cardiovascular: Atrial fibrillation, cardiomyopathy, colonic ischemia (see WARNINGS), 582 Prinzmetal variant angina, pulmonary embolism, shock, thrombophlebitis. 583 Ear, Nose, and Throat: Deafness. 584 Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis, loss of 585 vision. 586 Gastrointestinal: Ischemic colitis with rectal bleeding (see WARNINGS), xerostomia. 587 Hepatic: Elevated liver function tests. 588 Neurological: Central nervous system vasculitis, cerebrovascular accident, dysphasia, 589 subarachnoid hemorrhage. 590 Non-Site Specific: Angioneurotic edema, cyanosis, death (see WARNINGS), temporal 591 arteritis. 592 Psychiatry: Panic disorder. 593 Respiratory: Bronchospasm in patients with and without a history of asthma. 594 Skin: Exacerbation of sunburn, hypersensitivity reactions (allergic vasculitis, erythema, 595 pruritus, rash, shortness of breath, urticaria; in addition, severe anaphylaxis/anaphylactoid 596 reactions have been reported [see WARNINGS: Hypersensitivity]), photosensitivity. Following 597 subcutaneous administration of sumatriptan, pain, redness, stinging, induration, swelling, 598 contusion, subcutaneous bleeding, and, on rare occasions, lipoatrophy (depression in the skin) or 599 lipohypertrophy (enlargement or thickening of tissue) have been reported. 600 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 20 of 24 20 Urogenital: Acute renal failure. 601 DRUG ABUSE AND DEPENDENCE 602 The abuse potential of IMITREX Injection cannot be fully delineated in advance of extensive 603 marketing experience. One clinical study enrolling 12 patients with a history of substance abuse 604 failed to induce subjective behavior and/or physiologic response ordinarily associated with drugs 605 that have an established potential for abuse. 606 OVERDOSAGE 607 Patients (N = 269) have received single injections of 8 to 12 mg without significant adverse 608 effects. Volunteers (N = 47) have received single subcutaneous doses of up to 16 mg without 609 serious adverse events. 610 No gross overdoses in clinical practice have been reported. Coronary vasospasm was observed 611 after intravenous administration of IMITREX Injection (see CONTRAINDICATIONS). 612 Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause 613 convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, 614 ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and 615 paralysis. The half-life of elimination of sumatriptan is about 2 hours (see CLINICAL 616 PHARMACOLOGY: Pharmacokinetics), and therefore monitoring of patients after overdose 617 with IMITREX Injection should continue while symptoms or signs persist, and for at least 618 10 hours. 619 It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations 620 of sumatriptan. 621 DOSAGE AND ADMINISTRATION 622 The maximum single recommended adult dose of IMITREX Injection is 6 mg injected 623 subcutaneously. If side effects are dose limiting, then lower doses may be used (see Table 1). 624 The maximum recommended dose that may be given in 24 hours is two 6-mg injections 625 separated by at least 1 hour. Controlled clinical trials have failed to show that clear benefit is 626 associated with the administration of a second 6-mg dose in patients who have failed to respond 627 to a first injection. 628 In patients receiving MAO inhibitors, decreased doses of sumatriptan should be considered 629 (see WARNINGS: Concomitant Drug Use and CLINICAL PHARMACOLOGY: Drug 630 Interactions: Monoamine Oxidase Inhibitors). 631 An autoinjection device is available for use with the 4- and 6-mg prefilled syringe cartridges 632 to facilitate self-administration in patients using the 4- or 6-mg dose. With this device, the needle 633 penetrates approximately 1/4 inch (5 to 6 mm). Since the injection is intended to be given 634 subcutaneously, intramuscular or intravascular delivery should be avoided. Patients should be 635 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 21 of 24 21 directed to use injection sites with an adequate skin and subcutaneous thickness to accommodate 636 the length of the needle. 637 In patients receiving doses other than 4 or 6 mg, only the 6-mg single-dose vial dosage form 638 should be used. Parenteral drug products should be inspected visually for particulate matter and 639 discoloration before administration whenever solution and container permit. 640 HOW SUPPLIED 641 IMITREX Injection contains sumatriptan (base) as the succinate salt and is supplied as a clear, 642 colorless to pale yellow, sterile, nonpyrogenic solution as follows: 643 (NDC 0173-0739-00) IMITREX STATdose System®, 4 mg, containing 2 prefilled single-dose 644 syringe cartridges, 1 IMITREX STATdose Pen®, and instructions for use. 645 (NDC 0173-0739-02) Two 4-mg single-dose prefilled syringe cartridges for use with IMITREX 646 STATdose System. 647 (NDC 0173-0479-00) IMITREX STATdose System, 6 mg, containing 2 prefilled single-dose 648 syringe cartridges, 1 IMITREX STATdose Pen, and instructions for use. 649 (NDC 0173-0478-00) Two 6-mg single-dose prefilled syringe cartridges for use with IMITREX 650 STATdose System. 651 (NDC 0173-0449-02) IMITREX Injection single-dose vial (6 mg/0.5 mL) in cartons containing 5 652 vials. 653 Store between 2° and 30°C (36° and 86°F). Protect from light. 654 PATIENT INFORMATION 655 The following wording is contained in a separate leaflet provided for patients. 656 657 Information for the Patient 658 IMITREX® (sumatriptan succinate) Injection 659 660 Please read this leaflet carefully before you take IMITREX Injection. This leaflet provides a 661 summary of the information available about your medicine. Please do not throw away this leaflet 662 until you have finished your medicine. You may need to read this leaflet again. This leaflet does 663 not contain all the information on IMITREX Injection. For further information or advice, ask 664 your doctor or pharmacist. 665 Information About Your Medicine: 666 The name of your medicine is IMITREX (sumatriptan succinate) Injection. It can be obtained 667 only by prescription from your doctor. The decision to use IMITREX Injection is one that you 668 and your doctor should make jointly, taking into account your individual preferences and 669 medical circumstances. If you have risk factors for heart disease (such as high blood pressure, 670 high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are 671 postmenopausal or a male over 40), you should tell your doctor, who should evaluate you for 672 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 22 of 24 22 heart disease in order to determine if IMITREX is appropriate for you. Although the vast 673 majority of those who have taken IMITREX have not experienced any significant side effects, 674 some individuals have experienced serious heart problems and, rarely, considering the extensive 675 use of IMITREX worldwide, deaths have been reported. In all but a few instances, however, 676 serious problems occurred in people with known heart diseases and it was not clear whether 677 IMITREX was a contributory factor in these deaths. 678 1. The Purpose of Your Medicine: 679 IMITREX Injection is intended to relieve your migraine or cluster headache, but not to 680 prevent or reduce the number of attacks you experience. Use IMITREX Injection only to treat an 681 actual migraine or cluster headache attack. 682 2. Important Questions to Consider Before Taking IMITREX Injection: 683 If the answer to any of the following questions is YES or if you do not know the answer, then 684 please discuss with your doctor before you use IMITREX Injection. 685 • Are you pregnant? Do you think you might be pregnant? Are you trying to become pregnant? 686 Are you using inadequate contraception? Are you breastfeeding? 687 • Do you have any chest pain, heart disease, shortness of breath, or irregular heartbeats? Have 688 you had a heart attack? 689 • Do you have risk factors for heart disease (such as high blood pressure, high cholesterol, 690 obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal 691 or a male over 40)? 692 • Have you had a stroke, transient ischemic attacks (TIAs), or Raynaud syndrome? 693 • Do you have high blood pressure? 694 • Have you ever had to stop taking this or any other medicine because of an allergy or other 695 problems? 696 • Are you taking any other migraine medicines, including other 5-HT1 agonists or any other 697 medicines containing ergotamine, dihydroergotamine, or methysergide? 698 • Are you taking any medicine for depression (monoamine oxidase inhibitors or selective 699 serotonin reuptake inhibitors [SSRIs])? 700 • Have you had, or do you have, any disease of the liver or kidney? 701 • Have you had, or do you have, epilepsy or seizures? 702 • Is this headache different from your usual migraine attacks? 703 Remember, if you answered YES to any of the above questions, then discuss it with your 704 doctor. 705 3. The Use of IMITREX Injection During Pregnancy: 706 Do not use IMITREX Injection if you are pregnant, think you might be pregnant, are trying to 707 become pregnant, or are not using adequate contraception, unless you have discussed this with 708 your doctor. 709 4. How to Use IMITREX Injection: 710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 23 of 24 23 Before injecting IMITREX, check with your doctor on acceptable injection sites and see the 711 instructions inside the carton on discarding empty syringes and reloading an autoinjector device. 712 Never reuse a syringe. 713 For adults, the usual dose is a single injection given just below the skin. It should be given as 714 soon as the symptoms of your migraine appear, but it may be given at any time during an attack. 715 A second injection may be given if your symptoms of migraine come back. If your symptoms do 716 not improve following the first injection, do not give a second injection for the same attack 717 without first consulting with your doctor. Do not administer more than two 6-mg doses in any 718 24 hours and allow at least 1 hour between each dose. 719 5. Side Effects to Watch for: 720 • Some patients experience pain or tightness in the chest or throat when using IMITREX 721 Injection. If this happens to you, then discuss it with your doctor before using any more 722 IMITREX Injection. If the chest pain is severe or does not go away, call your doctor 723 immediately. 724 • If you have sudden and/or severe abdominal pain following IMITREX Injection, call your 725 doctor immediately. 726 • Shortness of breath; wheeziness; heart throbbing; swelling of eyelids, face, or lips; or a skin 727 rash, skin lumps, or hives happens rarely. If it happens to you, then tell your doctor 728 immediately. Do not take any more IMITREX Injection unless your doctor tells you to do so. 729 • Some people may have feelings of tingling, heat, flushing (redness of face lasting a short 730 time), heaviness or pressure after treatment with IMITREX Injection. A few people may feel 731 drowsy, dizzy, tired, or sick. Tell your doctor of these symptoms at your next visit. 732 • You may experience pain or redness at the site of injection, but this usually lasts less than an 733 hour. 734 • If you feel unwell in any other way or have any symptoms that you do not understand, you 735 should contact your doctor immediately. 736 6. What to Do if an Overdose Is Taken: 737 If you have taken more medicine than you have been told, contact either your doctor, hospital 738 emergency department, or nearest poison control center immediately. 739 7. Storing Your Medicine: 740 Keep your medicine in a safe place where children cannot reach it. It may be harmful to 741 children. 742 Store your medicine away from heat and light. Keep your medicine in the case provided and 743 do not store at temperatures above 86°F (30°C). 744 If your medicine has expired (the expiration date is printed on the treatment pack), throw it 745 away as instructed. Do not throw away your autoinjector. 746 If your doctor decides to stop your treatment, do not keep any leftover medicine unless your 747 doctor tells you to. Throw away your medicine as instructed. 748 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-080/S-036 Package Insert Page 24 of 24 24 749 750 751 GlaxoSmithKline 752 Research Triangle Park, NC 27709 753 754 ©2006, GlaxoSmithKline. All rights reserved. 755 756 January 2006 RL-2254 757 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Russell Katz 2/1/2006 11:15:03 AM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:41.035879	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020080s036lbl.pdf', 'application_number': 20080, 'submission_type': 'SUPPL ', 'submission_number': 36}
12,188	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IMITREX safely and effectively. See full prescribing information for IMITREX. IMITREX (sumatriptan succinate) injection, for subcutaneous use Initial U.S. Approval: 1992 ----------------------------INDICATIONS AND USAGE-------------------- IMITREX is a serotonin (5-HT1B/1D) receptor agonist (triptan) indicated for:  Acute treatment of migraine with or without aura in adults (1)  Acute treatment of cluster headache in adults (1) Limitations of Use:  Use only if a clear diagnosis of migraine or cluster headache has been established. (1)  Not indicated for the prevention of migraine attacks. (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------  For subcutaneous use only. (2.1)  Acute treatment of migraine: 1- to 6-mg Single dose. (2.1)  Acute treatment of cluster headache: 6-mg Single dose. (2.1)  Maximum dose in a 24-hour period: 12 mg, Separate doses by at least 1 hour. (2.1)  Patients receiving doses other than 4 or 6 mg: Use the 6-mg single-dose vial. (2.3) ---------------------DOSAGE FORMS AND STRENGTHS -------------  Injection: 4- and 6-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose Pen (3)  Injection: 6-mg single-dose vial (3) -------------------------------CONTRAINDICATIONS-----------------------  Coronary artery disease or coronary vasospasm (4)  Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders (4)  History of stroke, transient ischemic attack, or hemiplegic or basilar migraine (4)  Peripheral vascular disease (4)  Ischemic bowel disease (4)  Uncontrolled hypertension (4)  Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another triptan) or of an ergotamine-containing medication (4)  Ccurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor (4)  Known hypersensitivity to sumatriptan (4)  Severe hepatic impairment (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------  Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. (5.1)  Arrhythmias: Discontinue IMITREX if occurs. (5.2)  Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. (5.3)  Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue IMITREX if occurs. (5.4)  Gastrointestinal ischemia and infarction events, peripheral vasospastic reactions: Discontinue IMITREX if occurs. (5.5)  Medication overuse headache: Detoxification may be necessary. (5.6)  Serotonin syndrome: Discontinue IMITREX if occurs. (5.7)  Increase in blood pressure: Monitor blood pressure. (5.8)  Anaphylactic/anaphylactoid reactions: Discontinue IMITREX if occurs (5.9)  Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. (5.10) ------------------------------ ADVERSE REACTIONS ---------------------- Most common adverse reactions (5% and > placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------- USE IN SPECIFIC POPULATIONS ---------------  Pregnancy: Based on animal data, may cause fetal harm (8.1)  Geriatric use: A cardiovascular evaluation is recommended in those who have other cardiovascular risk factors prior to receiving IMITREX. (8.5) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 09/2012 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Administration Using the IMITREX STATdose Pen ® 2.3 Administration of Doses of IMITREX Other Than 4 or 6 mg 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina 5.2 Arrhythmias 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 5.4 Cerebrovascular Events 5.5 Other Vasospasm Reactions 5.6 Medication Overuse Headache 5.7 Serotonin Syndrome 5.8 Increase in Blood Pressure 5.9 Anaphylactic/Anaphylactoid Reactions 5.10 Seizures 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Ergot-Containing Drugs 7.2 Monoamine Oxidase-A Inhibitors 7.3 Other 5-HT1 Agonists 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Migraine 14.2 Cluster Headache 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events 17.2 Anaphylactic/Anaphylactoid Reactions 17.3 Medication Overuse Headache 17.4 Pregnancy 17.5 Nursing Mothers 17.6 Ability To Perform Complex Tasks 1 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 10 15 20 25 30 35 17.7 Serotonin Syndrome *Sections or subsections omitted from the full prescribing information are not 17.8 How to Use IMITREX Injection listed. 1 FULL PRESCRIBING INFORMATION 2 1 INDICATIONS AND USAGE 3 IMITREX® Injection is indicated in adults for (1) the acute treatment of migraine, with or 4 without aura, and (2) the acute treatment of cluster headache. Limitations of Use: 6  Use only if a clear diagnosis of migraine or cluster headache has been established. 7  If a patient has no response to the first migraine attack treated with IMITREX, reconsider the 8 diagnosis of migraine before IMITREX is administered to treat any subsequent attacks. 9  IMITREX is not indicated for the prevention of migraine attacks. 2 DOSAGE AND ADMINISTRATION 11 2.1 Dosing Information 12 The maximum single recommended adult dose of IMITREX Injection for the acute 13 treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of 14 migraine, if side effects are dose limiting, lower doses (1 to 5 mg) may be used [see Clinical Studies (14.1)]. For the treatment of cluster headache, the efficacy of lower doses has not been 16 established. 17 The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg 18 injections separated by at least 1 hour. A second 6-mg dose should only be considered if some 19 response to a first injection was observed. 2.2 Administration Using the IMITREX STATdose Pen® 21 An autoinjector device (IMITREX STATdose Pen) is available for use with 4- and 6-mg 22 prefilled syringe cartridges. With this device, the needle penetrates approximately 1/4 inch (5 to 23 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular 24 delivery must be avoided. Instruct patients on the proper use of IMITREX STATdose Pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to 26 accommodate the length of the needle. 27 2.3 Administration of Doses of IMITREX Other Than 4 or 6 mg 28 In patients receiving doses other than 4 or 6 mg, use the 6-mg single-dose vial; do not use 29 the IMITREX STATdose Pen. Visually inspect the vial for particulate matter and discoloration before administration. Do not use if particulates and discolorations are noted. 31 3 DOSAGE FORMS AND STRENGTHS 32  Injection: 4- and 6-mg single-dose prefilled syringe cartridges for use with the IMITREX 33 STATdose Pen 34  Injection: 6-mg single-dose vial 4 CONTRAINDICATIONS 36 IMITREX Injection is contraindicated in patients with: 2 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 37  Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or 38 documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina 39 [see Warnings and Precautions (5.1)]. 40  Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory 41 conduction pathway disorders [see Warnings and Precautions (5.2)]. 42  History of stroke or transient ischemic attack (TIA) because these patients are at a higher risk 43 of stroke [see Warnings and Precautions (5.4)]. 44  History of hemiplegic or basilar migraine. 45  Peripheral vascular disease [see Warnings and Precautions (5.5)]. 46  Ischemic bowel disease [see Warnings and Precautions (5.5)]. 47  Uncontrolled hypertension [see Warnings and Precautions (5.8)]. 48  Recent (i.e., within 24 hours) use of ergotamine-containing medication, ergot-type 49 medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 50 (5-HT1) agonist [see Drug Interactions (7.1, 7.3)]. 51  Concurrent administration of an MAO-A inhibitor or recent (within 2 weeks) use of an 52 MAO-A inhibitor [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 53  Known hypersensitivity to sumatriptan [see Warnings and Precautions (5.9) and Adverse 54 Reactions (6.2)]. 55  Severe hepatic impairment [see Clinical Pharmacology (12.3)]. 56 5 WARNINGS AND PRECAUTIONS 57 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina 58 The use of IMITREX Injection is contraindicated in patients with ischemic or vasospastic 59 CAD. There have been rare reports of serious cardiac adverse reactions, including acute 60 myocardial infarction, occurring within a few hours following administration of IMITREX 61 Injection. Some of these reactions occurred in patients without known CAD. 5-HT1 agonists, 62 including IMITREX Injection, may cause coronary artery vasospasm (Prinzmetal’s angina), even 63 in patients without a history of CAD. 64 Perform a cardiovascular evaluation in triptan-naive patients who have multiple 65 cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong 66 family history of CAD) prior to receiving IMITREX Injection. If there is evidence of CAD or 67 coronary artery vasospasm, IMITREX Injection is contraindicated. For patients with multiple 68 cardiovascular risk factors who have a negative cardiovascular evaluation, consider 69 administering the first dose of IMITREX Injection in a medically supervised setting and 70 performing an electrocardiogram (ECG) immediately following IMITREX Injection. For such 71 patients, consider periodic cardiovascular evaluation in intermittent long-term users of IMITREX 72 Injection. 73 Evaluate patients with signs or symptoms suggestive of angina following IMITREX 74 Injection for the presence of CAD or Prinzmetal’s angina before receiving additional doses of 75 IMITREX Injection. Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 76 5.2 Arrhythmias 77 Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and 78 ventricular fibrillation leading to death, have been reported within a few hours following the 79 administration of 5-HT1 agonists. Discontinue IMITREX Injection if these disturbances occur. 80 IMITREX Injection is contraindicated in patients with Wolff-Parkinson-White syndrome or 81 arrhythmias associated with other cardiac accessory conduction pathway disorders 82 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 83 As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the 84 precordium, throat, neck, and jaw commonly occur after treatment with IMITREX Injection and 85 are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at 86 high cardiac risk. The use of IMITREX Injection is contraindicated in patients shown to have 87 CAD and those with Prinzmetal’s variant angina. 88 5.4 Cerebrovascular Events 89 Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients 90 treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears 91 possible that the cerebrovascular events were primary, the 5-HT1 agonist having been 92 administered in the incorrect belief that the symptoms experienced were a consequence of 93 migraine when they were not. Also, patients with migraine may be at increased risk of certain 94 cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue IMITREX Injection if a 95 cerebrovascular event occurs. 96 As with other acute migraine therapies, before treating headaches in patients not 97 previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, 98 exclude other potentially serious neurological conditions. IMITREX Injection is contraindicated 99 in patients with a history of stroke or TIA. 100 5.5 Other Vasospasm Reactions 101 5-HT1 agonists, including IMITREX Injection, may cause non-coronary vasospastic 102 reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction 103 (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s 104 syndrome. Until further evaluation, IMITREX Injection is contraindicated in patients who 105 experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use 106 of any 5-HT1 agonist. 107 Reports of transient and permanent blindness and significant partial vision loss have been 108 reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, 109 a causal relationship between these events and the use of 5-HT1 agonists have not been clearly 110 established. 111 5.6 Medication Overuse Headache 112 Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, combination of 113 drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse 114 headache). Medication overuse headache may present as migraine-like daily headaches, or as a 115 marked increase in frequency of migraine attacks. Detoxification of patients, including 4 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 116 withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes 117 a transient worsening of headache) may be necessary. 118 5.7 Serotonin Syndrome 119 Serotonin syndrome may occur with triptans, including IMITREX Injection, particularly 120 during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin 121 norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO 122 inhibitors [see Drug Interactions (7.4)]. Serotonin syndrome symptoms may include mental 123 status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, 124 labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, 125 incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of 126 symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a 127 serotonergic medication. Discontinue IMITREX Injection if serotonin syndrome is suspected. 128 5.8 Increase in Blood Pressure 129 Significant elevation in blood pressure, including hypertensive crisis with acute 130 impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 131 agonists, including patients without a history of hypertension. Monitor blood pressure in patients 132 treated with IMITREX. IMITREX Injection is contraindicated in patients with uncontrolled 133 hypertension. 134 5.9 Anaphylactic/Anaphylactoid Reactions 135 Anaphylactic/anaphylactoid reactions have occurred in patients receiving sumatriptan. 136 Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are 137 more likely to occur in individuals with a history of sensitivity to multiple allergens. IMITREX 138 Injection is contraindicated in patients with prior serious anaphylactic reaction. 139 5.10 Seizures 140 Seizures have been reported following administration of sumatriptan. Some have 141 occurred in patients with either a history of seizures or concurrent conditions predisposing to 142 seizures. There are also reports in patients where no such predisposing factors are apparent. 143 IMITREX Injection should be used with caution in patients with a history of epilepsy or 144 conditions associated with a lowered seizure threshold. 145 6 ADVERSE REACTIONS 146 The following adverse reactions are discussed in more detail in other sections of the 147 labeling: 148  Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina [see Warnings and 149 Precautions (5.1)] 150  Arrhythmias [see Warnings and Precautions (5.2)] 151  Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)] 152  Cerebrovascular events [see Warnings and Precautions (5.4)] 153  Other vasospasm reactions [see Warnings and Precautions (5.5)] 154  Medication overuse headache [see Warnings and Precautions (5.6)] Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 155  Serotonin syndrome [see Warnings and Precautions (5.7)] 156  Increase in blood pressure [see Warnings and Precautions (5.8)] 157  Anaphylactic/anaphylactoid reactions [see Warnings and Precautions (5.9)] 158  Seizures [see Warnings and Precautions (5.10)] 159 6.1 Clinical Trials Experience 160 Because clinical trials are conducted under widely varying conditions, adverse reaction 161 rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical 162 trials of another drug and may not reflect the rates observed in practice. 163 Migraine Headache: Table 1 lists adverse reactions that occurred in 2 US 164 placebo-controlled clinical trials in migraine subjects [Studies 2 and 3, see Clinical Studies 165 (14.1)] following either a single 6-mg dose of IMITREX Injection or placebo. Only reactions 166 that occurred at a frequency of 2% or more in groups treated with IMITREX Injection 6 mg and 167 that occurred at a frequency greater than the placebo group are included in Table 1. 168 169 Table 1. Adverse Reactions Reported by at Least 2% of Subjects and at a Greater 170 Frequency Than Placebo in 2 Placebo-Controlled Migraine Clinical Trials (Studies 2 171 and 3)a Adverse Reaction Percent of Subjects Reporting IMITREX Injection 6 mg Subcutaneous (n = 547) Placebo (n = 370) Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort Tightness in chest Pressure in chest 5 3 2 1 <1 <1 Ear, nose, and throat Throat discomfort Discomfort: nasal cavity/sinuses 3 2 <1 <1 Injection site reactionb 59 24 6 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness Neck pain/stiffness Myalgia 5 5 2 <1 <1 <1 Neurological Dizziness/vertigo Drowsiness/sedation Headache 12 3 2 4 2 <1 Skin Sweating 2 1 172 a The sum of the percentages cited is greater than 100% because subjects may have 173 experienced more than 1 type of adverse reaction. Only reactions that occurred at a 174 frequency of 2% or more in groups treated with IMITREX Injection and occurred at a 175 frequency greater than the placebo groups are included. 176 b Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding. 177 178 The incidence of adverse reactions in controlled clinical trials was not affected by gender 179 or age of the subjects. There were insufficient data to assess the impact of race on the incidence 180 of adverse reactions. 181 Cluster Headache: In the controlled clinical trials assessing the efficacy of IMITREX 182 Injection as a treatment for cluster headache [Studies 4 and 5, see Clinical Studies (14.2)], no 183 new significant adverse reactions were detected that had not already been identified in trials of 184 IMITREX in subjects with migraine. 185 Overall, the frequency of adverse reactions reported in the trials of cluster headache was 186 generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% 187 IMITREX, 0% placebo), nausea and vomiting (4% IMITREX, 0% placebo), and bronchospasm 188 (1% IMITREX, 0% placebo). 189 Other Adverse Reactions: In the paragraphs that follow, the frequencies of less 190 commonly reported adverse reactions are presented. Reaction frequencies were calculated as the 191 number of subjects reporting a reaction divided by the total number of subjects (N = 6,218) 192 exposed to subcutaneous IMITREX Injection. All reported reactions are included except those 193 already listed in the previous table. Reactions are further classified within body system 194 categories and enumerated in order of decreasing frequency using the following definitions: 195 frequent are defined as those occurring in at least 1/100 subjects, infrequent are those occurring 196 in 1/100 to 1/1,000 subjects, and rare are those occurring in fewer than 1/1,000 subjects. 197 Cardiovascular: Infrequent were hypertension, hypotension, bradycardia, tachycardia, 198 palpitations, and syncope. Rare was arrhythmia. 199 Gastrointestinal: Frequent was abdominal discomfort. 7 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 200 Musculoskeletal: Frequent were muscle cramps. 201 Neurological: Frequent was anxiety. Infrequent were mental confusion, euphoria, 202 agitation, tremor. Rare were myoclonia, sleep disturbance, and dystonia. 203 Respiratory: Infrequent was dyspnea. 204 Skin: Infrequent were erythema, pruritus, and skin rashes. 205 Miscellaneous: Infrequent was “serotonin agonist effect”. 206 Adverse Events Observed With Other Formulations of IMITREX: The following 207 adverse events occurred in clinical trials with IMITREX® Tablets and IMITREX® Nasal Spray. 208 Because the reports include events observed in open and uncontrolled trials, the role of 209 IMITREX in their causation cannot be reliably determined. All reported events are included 210 except those already listed, those too general to be informative, and those not reasonably 211 associated with the use of the drug. 212 Cardiovascular: Angina, cerebrovascular lesion, heart block, peripheral cyanosis, 213 phlebitis, thrombosis. 214 Gastrointestinal: Abdominal distention and colitis. 215 Neurological: Convulsions, hallucinations, syncope, suicide, and twitching. 216 Miscellaneous: Edema, hypersensitivity, swelling of extremities, and swelling of 217 face. 218 6.2 Postmarketing Experience 219 The following adverse reactions have been identified during postapproval use of 220 IMITREX Tablets, IMITREX Nasal Spray, and IMITREX Injection. Because these reactions are 221 reported voluntarily from a population of uncertain size, it is not always possible to reliably 222 estimate their frequency or establish a causal relationship to drug exposure. These reactions have 223 been chosen for inclusion due to either their seriousness, frequency of reporting, or causal 224 connection to IMITREX or a combination of these factors. 225 Blood: Hemolytic anemia, pancytopenia, thrombocytopenia. 226 Ear, Nose, and Throat: Deafness. 227 Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis. 228 Neurological: Central nervous system vasculitis, cerebrovascular accident, serotonin 229 syndrome, subarachnoid hemorrhage. 230 Non-Site Specific: Angioedema, cyanosis, temporal arteritis. 231 Skin: Exacerbation of sunburn, hypersensitivity reactions (allergic vasculitis, erythema, 232 pruritus, rash, shortness of breath, urticaria), photosensitivity. Following subcutaneous 233 administration of IMITREX, pain, redness, stinging, induration, swelling, contusion, 234 subcutaneous bleeding, and, on rare occasions, lipoatrophy (depression in the skin) or 235 lipohypertrophy (enlargement or thickening of tissue) have been reported. 236 Urogenital: Acute renal failure. 237 7 DRUG INTERACTIONS 238 7.1 Ergot-Containing Drugs Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 239 Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. 240 Because these effects may be additive, use of ergotamine-containing or ergot-type medications 241 (like dihydroergotamine or methysergide) and IMITREX Injection within 24 hours of each other 242 is contraindicated. 243 7.2 Monoamine Oxidase-A Inhibitors 244 MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of IMITREX 245 Injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology 246 (12.3)]. 247 7.3 Other 5-HT1 Agonists 248 Because their vasospastic effects may be additive, coadministration of IMITREX 249 Injection and other 5-HT1 agonists (e.g., triptans) within 24 hours of each other is 250 contraindicated. 251 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine 252 Reuptake Inhibitors and Serotonin Syndrome 253 Cases of serotonin syndrome have been reported during coadministration of triptans and 254 SSRIs, or SNRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)]. 255 8 USE IN SPECIFIC POPULATIONS 256 8.1 Pregnancy 257 Pregnancy Category C: There are no adequate and well-controlled trials of IMITREX 258 Injection in pregnant women. IMITREX Injection should be used during pregnancy only if the 259 potential benefit justifies the potential risk to the fetus. 260 When sumatriptan was administered intravenously to pregnant rabbits daily throughout 261 the period of organogenesis, embryolethality was observed at doses at or close to those 262 producing maternal toxicity. These doses were less than the maximum recommended human 263 dose (MRHD) of 12 mg/day on a mg/m2 basis. Oral administration of sumatriptan to rabbits 264 during organogenesis was associated with increased incidences of fetal vascular and skeletal 265 abnormalities. The highest no-effect dose for these effects was 15 mg/kg/day. The intravenous 266 administration of sumatriptan to pregnant rats throughout organogenesis at doses that are 267 approximately 10 times the MRHD on a mg/m2 basis, did not produce evidence of 268 embryolethality. The subcutaneous administration of sumatriptan to pregnant rats prior to and 269 throughout pregnancy did not produce evidence of embryolethality or teratogenicity. 270 8.3 Nursing Mothers 271 It is not known whether sumatriptan is excreted in human breast milk following 272 subcutaneous administration. Because many drugs are excreted in human milk, and because of 273 the potential for serious adverse reactions in nursing infants from IMITREX, a decision should 274 be made whether to discontinue nursing or to discontinue the drug, taking into account the 275 importance of the drug to the mother. 276 8.4 Pediatric Use Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 277 Safety and effectiveness of IMITREX Injection in pediatric patients under 18 years of 278 age have not been established; therefore, IMITREX Injection is not recommended for use in 279 patients under 18 years of age. 280 Two controlled clinical trials evaluated IMITREX Nasal Spray (5 to 20 mg) in 1,248 281 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not 282 establish the efficacy of IMITREX Nasal Spray compared with placebo in the treatment of 283 migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature 284 to those reported in clinical trials in adults. 285 Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating 286 oral IMITREX (25 to 100 mg) in pediatric subjects aged 12 to 17 years enrolled a total of 701 287 adolescent migraineurs. These trials did not establish the efficacy of oral IMITREX compared 288 with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these 289 clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of 290 all adverse reactions in these subjects appeared to be both dose- and age-dependent, with 291 younger subjects reporting reactions more commonly than older adolescents. 292 Postmarketing experience documents that serious adverse reactions have occurred in the 293 pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. These reports 294 include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, 295 and death. A myocardial infarction has been reported in a 14-year-old male following the use of 296 oral IMITREX; clinical signs occurred within 1 day of drug administration. Since clinical data to 297 determine the frequency of serious adverse reactions in pediatric patients who might receive 298 subcutaneous, oral, or intranasal IMITREX are not presently available, the use of IMITREX in 299 patients under 18 years of age is not recommended. 300 8.5 Geriatric Use 301 Clinical trials of IMITREX Injection did not include sufficient numbers of subjects aged 302 65 and over to determine whether they respond differently from younger subjects. Other reported 303 clinical experience has not identified differences in responses between the elderly and younger 304 subjects. In general, dose selection for an elderly patient should be cautious, usually starting at 305 the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or 306 cardiac function and of concomitant disease or other drug therapy. 307 A cardiovascular evaluation is recommended for geriatric patients who have other 308 cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history 309 of CAD) prior to receiving IMITREX Injection [see Warnings and Precautions (5.1)]. 310 10 OVERDOSAGE 311 No gross overdoses in clinical practice have been reported. Coronary vasospasm was 312 observed after intravenous administration of IMITREX Injection [see Contraindications (4)]. 313 Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly 314 cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 315 cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), 316 and paralysis. 317 The elimination half-life of sumatriptan is about 2 hours [see Clinical Pharmacology 318 (12.3)], and therefore monitoring of patients after overdose with IMITREX Injection should 319 continue for at least 10 hours or while symptoms or signs persist. 320 It is unknown what effect hemodialysis or peritoneal dialysis has on the serum 321 concentrations of sumatriptan. 322 11 DESCRIPTION 323 IMITREX Injection contains sumatriptan succinate, a selective 5-HT1B/1D receptor 324 agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N 325 methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: 326 structural formula 327 328 329 The empirical formula is C14H21N3O2SC4H6O4, representing a molecular weight of 330 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in 331 saline. 332 IMITREX Injection is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for 333 subcutaneous injection. Each 0.5 mL of IMITREX Injection 8 mg/mL solution contains 4 mg of 334 sumatriptan (base) as the succinate salt and 3.8 mg of sodium chloride, USP in Water for 335 Injection, USP. Each 0.5 mL of IMITREX Injection 12 mg/mL solution contains 6 mg of 336 sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for 337 Injection, USP. The pH range of both solutions is approximately 4.2 to 5.3. The osmolality of 338 both injections is 291 mOsmol. 339 12 CLINICAL PHARMACOLOGY 340 12.1 Mechanism of Action 341 Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. IMITREX 342 presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 343 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal 344 system. 345 Current theories proposed to explain the etiology of migraine headache suggest that 346 symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides 347 (including substance P and calcitonin gene-related peptide) through nerve endings in the 348 trigeminal system. The therapeutic activity of IMITREX for the treatment of migraine and 349 cluster headaches is thought to be due to the agonist effects at the 5-HT1B/1D receptors on 11 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 350 intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves o f the 351 trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory 352 neuropeptide release. 353 12.2 Pharmacody namics 354 Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, 355 has been reported in patients with and without a history of hypertension [see Warnings and 356 Precautions (5.8)]. 357 Peripheral (Small) Arteries: In healthy volunteers (N = 18), a trial evaluating the effects 358 o f suma triptan on peripheral (small vessel) arterial reactivity failed to detect a clinically 359 significant increase in peripheral resistance. 360 Heart Rate: Transient increases in blood pressure observed in some subjects in clinical 361 trials carried out during sumatriptan’s development as a treatment for migraine were not 362 accompanied by any clinically significant changes in heart rate. 363 12.3 Pharmacokinetics 364 Absorption and Bioavailability: The bioavailability of sumatriptan via subcutaneous site 365 injection to 18 healthy male subjects was 97%  16% of that obtained following intravenous 366 injection. 367 Aft er a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 368 healthy males (age: 24  6 years, weight: 70 kg), the maximum serum concentration (Cmax) of 369 sumatriptan was (mean  standard deviation) 74  15 ng/mL and the time to peak concentration 370 (Tmax) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected 371 subcutaneously in the thigh gave a Cmax of 61  15 ng/mL by manual injection versus 52  372 15 ng/mL by autoinjector techniques. The Tmax or amount absorbed was not significantly alt ered 373 by either the site or technique of injection. 374 Distribution: Protein binding, determined by equilibrium dialysis over the concentration 375 range of 10 to 1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the 376 protein binding of other drugs has not been evaluated. 377 Following a 6-mg subcutaneous injection into th e deltoid area of the arm in 9 males 378 ( mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of 379 sumatriptan was 50  8 liters and the distribution half-life was 15  2 minutes. 380 Metabolism: In vitro studies with human microsomes suggest that sumatriptan is 381 m etabo lized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of 382 sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA 383 glucuronide, both of which are inactive. 384 Elimination: After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine 385 as unchanged sumatriptan and 38%  7% as the IAA metabolite. 386 Following a 6-mg subcutaneous injection into the deltoid a rea of the arm, the systemic 387 clearance of sumatriptan was 1,194  149 mL/min and the terminal half-life was 115  388 19 minutes. Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 389 Special Populations: Age: The pharmacokinetics of sumatriptan in the elderly (mean 390 age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 391 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). 392 Renal Impairment: The effect of renal impairment on the pharmacokinetics of 393 sumatriptan has not been examined. 394 Hepatic Impairment: The effect of mild to moderate hepatic disease on the 395 pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were 396 no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in 397 moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics 398 of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not 399 been studied. The use of IMITREX Injection in this population is contraindicated [see 400 Contraindications (4)]. 401 Race: The systemic clearance and Cmax of sumatriptan were similar in black (n = 34) 402 and Caucasian (n = 38) healthy male subjects. 403 Drug Interaction Studies: Monoamine Oxidase-A Inhibitors: In a trial of 14 healthy 404 females, pretreatment with an MAO-A inhibitor decreased the clearance of sumatriptan, resulting 405 in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), 406 corresponding to a 40% increase in elimination half-life. 407 13 NONCLINICAL TOXICOLOGY 408 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 409 Carcinogenesis: In carcinogenicity studies, rats and mice were given sumatriptan by 410 oral gavage. Mice were dosed for 78 weeks and rats were dosed for 104 weeks. Average 411 exposures achieved in mice receiving the highest dose were approximately 110 times the 412 exposure attained in humans after the maximum recommended single dose of 6 mg. The highest 413 dose to rats was approximately 260 times the maximum single dose of 6 mg on a mg/m2 basis. 414 There was no evidence of an increase in tumors in either species related to sumatriptan 415 administration. 416 Mutagenesis: Sumatriptan was not mutagenic in the presence or absence of metabolic 417 activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian 418 Chinese hamster V79/HGPRT assay). It was not clastogenic in 2 cytogenetics assays (the in vitro 419 human lymphocyte assay and the in vivo rat micronucleus assay). 420 Impairment of Fertility: A fertility study (Segment I) by the subcutaneous route, during 421 which male and female rats were dosed daily with sumatriptan prior to and throughout the 422 mating period, has shown no evidence of impaired fertility at doses equivalent to approximately 423 100 times the maximum recommended single human dose of 6 mg on a mg/m2 basis. However, 424 following oral administration, a treatment-related decrease in fertility, secondary to a decrease in 425 mating, was seen for rats treated with 50 and 500 mg/kg/day. The no-effect dose for this finding 426 was approximately 8 times the maximum recommended single human dose of 6 mg on a mg/m2 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 427 basis. It is not clear whether the problem is associated with the treatment of males or females or 428 both. 429 13.2 Animal Toxicology and/or Pharmacology 430 Corneal Opacities: Dogs receiving oral sumatriptan developed corneal opacities and 431 defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 432 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium 433 were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and 434 no-effect doses were not established; however, the relative exposure at the lowest dose tested 435 was approximately 5 times the human exposure after a 100-mg oral dose or 3 times the human 436 exposure after a 6-mg subcutaneous dose. 437 Melanin Binding: In rats with a single subcutaneous dose (0.5 mg/kg) of radiolabeled 438 sumatriptan, the elimination half-life of radioactivity from the eye was 15 days, suggesting that 439 sumatriptan and its metabolites bind to the melanin of the eye. The clinical significance of this 440 binding is unknown. 441 14 CLINICAL STUDIES 442 14.1 Migraine 443 In controlled clinical trials enrolling more than 1,000 subjects during migraine attacks 444 who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in 445 Table 3, onset of relief began as early as 10 minutes following a 6-mg IMITREX Injection. 446 Lower doses of IMITREX Injection may also prove effective, although the proportion of subjects 447 obtaining adequate relief was decreased and the latency to that relief is greater with lower doses. 448 In Study 1, 6 different doses of IMITREX Injection (n = 30 each group) were compared 449 with placebo (n = 62), in a single-attack, parallel-group design, the dose response relationship 450 was found to be as shown in Table 2. 451 452 Table 2. Proportion of Subjects With Migraine Relief and Incidence of Adverse Events by 453 Time and by IMITREX Dose in Study 1 Dose of IMITREX Injection Percent Subjects With Reliefa Adverse Events Incidence (%) at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours Placebo 1 mg 2 mg 3 mg 4 mg 6 mg 8 mg 5 10 7 17 13 10 23 15 40 23 47 37 63 57 24 43 57 57 50 73 80 21 40 43 60 57 70 83 55 63 63 77 80 83 93 454 a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing 455 without use of rescue medication. Reference ID: 3198130 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 456 457 In 2 randomized, placebo-controlled clinical trials of IMITREX Injection 6 mg in 1,104 458 subjects with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 459 10 minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe 460 to mild or no headache, was achieved in 70% of the subjects within 1 hour of a single 6-mg 461 subcutaneous dose of IMITREX Injection. Approximately 82% and 65% of subjects treated with 462 IMITREX 6 mg had headache relief and were pain free within 2 hours, respectively. 463 Table 3 shows the 1- and 2-hour efficacy results for IMITREX Injection 6 mg in Studies 464 2 and 3. 465 466 Table 3. Proportion of Subjects With Pain Relief and Relief of Migraine Symptoms After 1 467 and 2 Hours of Treatment in Studies 2 and 3 1-Hour Data Study 2 Study 3 Placebo (n = 190) IMITREX 6 mg (n = 384) Placebo (n = 180) IMITREX 6 mg (n = 350) Subjects with pain relief (grade 0/1) 18% 70%a 26% 70%a Subjects with no pain 5% 48%a 13% 49%a Subjects without nausea 48% 73%a 50% 73%a Subjects without photophobia Subjects with little or no clinical 23% 56%a 25% 58%a disabilityb 34% 76%a 34% 76%a 2-Hour Data Study 2 Study 3 Placeboc IMITREX 6 mgd Placeboc IMITREX 6 mgd Subjects with pain relief (grade 0/1) 31% 81%a 39% 82%a Subjects with no pain 11% 63%a 19% 65%a Subjects without nausea 56% 82%a 63% 81%a Subjects without photophobia 31% 72%a 35% 71%a Subjects with little or no clinical disabilityb 42% 85%a 49% 84%a 468 a P<0.05 versus placebo. 469 b A successful outcome in terms of clinical disability was defined prospectively as ability to 470 work mildly impaired or ability to work and function normally. 471 c Includes subjects that may have received an additional placebo injection 1 hour after the initial 472 injection. 473 d Includes subjects that may have received an additional 6 mg of IMITREX Injection 1 hour 474 after the initial injection. 475 15 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 476 IMITREX Injection also relieved photophobia, phonophobia (sound sensitivity), nausea, 477 and vomiting associated with migraine attacks. Similar efficacy was seen when subjects 478 self-administered IMITREX Injection using the IMITREX STATdose Pen. 479 The efficacy of IMITREX Injection was unaffected by whether or not the migraine was 480 associated with aura, duration of attack, gender or age of the subject, or concomitant use of 481 common migraine prophylactic drugs (e.g., beta-blockers). 482 14.2 Cluster Headache 483 The efficacy of IMITREX Injection in the acute treatment of cluster headache was 484 demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period crossover trials 485 (Studies 4 and 5). Subjects aged 21 to 65 years were enrolled and were instructed to treat a 486 moderate to very severe headache within 10 minutes of onset. Headache relief was defined as a 487 reduction in headache severity to mild or no pain. In both trials, the proportion of individuals 488 gaining relief at 10 or 15 minutes was significantly greater among subjects receiving 6 mg of 489 IMITREX Injection compared with those who received placebo (see Table 4). 490 491 Table 4. Proportion of Subjects With Cluster Headache Relief by Time in Studies 4 and 5 Study 4 Study 5 Placebo (n = 39) IMITREX 6 mg (n = 39) Placebo (n = 88) IMITREX 6 mg (n = 92) Subjects with pain relief (no/mild) 5 Minutes post-injection 10 Minutes post-injection 15 Minutes post-injection 8% 10% 26% 21% 49%a 74%a 7% 25% 35% 23%a 49%a 75%a 492 a P<0.05. 493 (n = Number of headaches treated.) 494 495 An estimate of the cumulative probability of a subject with a cluster headache obtaining 496 relief after being treated with either IMITREX Injection or placebo is presented in Figure 1. 497 16 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 498 Figure 1. Time to Relief of Cluster Headache from Time of Injectiona 499 graph 501 a The figure uses Kaplan-Meier (product limit) Survivorship Plot. Subjects taking rescue 502 medication were censored at 15 minutes. 503 504 The plot was constructed with data from subjects who either experienced relief or did not 505 require (request) rescue medication within a period of 2 hours following treatment. As a 506 consequence, the data in the plot are derived from only a subset of the 258 headaches treated 507 (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 508 headaches treated with IMITREX Injection). 509 Other data suggest that treatment with IMITREX Injection is not associated with an 510 increase in early recurrence of headache and has little effect on the incidence of later-occurring 511 headaches (i.e., those occurring after 2, but before 18 or 24 hours). 512 16 HOW SUPPLIED/STORAGE AND HANDLING 513 IMITREX Injection contains sumatriptan (base) as the succinate salt and is supplied as a 514 clear, colorless to pale yellow, sterile, nonpyrogenic solution as follows: 515 Prefilled Syringe and/or Autoinjector Pen: Each pack contains a Patient Information and Patients 516 Instructions for Use leaflet. 517  IMITREX STATdose System®, 4 mg, containing 1 IMITREX STATdose Pen, 2 prefilled 518 single-dose syringe cartridges, and 1 carrying case (NDC 0173-0739-00). 519  IMITREX STATdose System, 6 mg, containing 1 IMITREX STATdose Pen, 2 prefilled 520 single-dose syringe cartridges, and 1 carrying case (NDC 0173-0479-00). 521  Two 4-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose System 522 (NDC 0173-0739-02). 523  Two 6-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose System 524 (NDC 0173-0478-00). 17 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 525 Single-Dose Vial: 526  IMITREX Injection single-dose vial (6 mg/0.5 mL) in cartons containing 5 vials (NDC 0173 527 0449-02). 528 Store between 2° and 30°C (36° and 86°F). Protect from light. 529 17 PATIENT COUNSELING INFORMATION 530 See FDA-approved patient labeling (Patient Information and Instructions for Use). 531 17.1 Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other 532 Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events 533 Inform patients that IMITREX Injection may cause serious cardiovascular side effects 534 such as myocardial infarction or stroke. Although serious cardiovascular events can occur 535 without warning symptoms, patients should be alert for the signs and symptoms of chest pain, 536 shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring 537 of speech and should ask for medical advice when observing any indicative sign or symptoms. 538 Patients should be apprised of the importance of this follow-up [see Warnings and Precautions 539 (5.1, 5.2, 5.4, 5.5, 5.8)]. 540 17.2 Anaphylactic/Anaphylactoid Reactions 541 Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients 542 receiving IMITREX Injection. Such reactions can be life threatening or fatal. In general, 543 anaphylactic reactions to drugs are more likely to occur in individuals with a history of 544 sensitivity to multiple allergens [see Warnings and Precautions (5.9)]. 545 17.3 Medication Overuse Headache 546 Inform patients that use of acute migraine drugs for 10 or more days per month may lead 547 to an exacerbation of headache and encourage patients to record headache frequency and drug 548 use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)]. 549 17.4 Pregnancy 550 Inform patients that IMITREX Injection should not be used during pregnancy unless the 551 potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. 552 17.5 Nursing Mothers 553 Advise patients to notify their healthcare provider if they are breastfeeding or plan to 554 breastfeed [see Use in Specific Populations (8.3)]. 555 17.6 Ability To Perform Complex Tasks 556 Since migraines or treatment with IMITREX Injection may cause somnolence and 557 dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine 558 attacks and after administration of IMITREX Injection. 559 17.7 Serotonin Syndrome 560 Patients should be cautioned about the risk of serotonin syndrome with the use of 561 IMITREX Injection or other triptans, particularly during combined use with SSRIs, SNRIs, 562 TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) and Drug Interactions (7.4)]. 563 17.8 How to Use IMITREX Injection Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c ompany logo 564 Provide patients instruction on the proper use of IMITREX Injection if they are able to 565 self-administer IMITREX Injection in medically unsupervised situation. 566 Inform patients that the needle in the IMITREX STATdose Pen penetrates approximately 567 1/4 of an inch (5 to 6 mm). Inform patients that the injection is intended to be given 568 subcutaneously and intramuscular or intravascular delivery should be avoided. Instruct patients 569 to use injection sites with an adequate skin and subcutaneous thickness to accommodate the 570 length of the needle. 571 572 IMITREX, IMITREX STATdose Pen, and IMITREX STATdose System are registered 573 trademarks of GlaxoSmithKline. 574 575 576 577 GlaxoSmithKline 578 Research Triangle Park, NC 27709 579 580 ©2012, GlaxoSmithKline. All rights reserved. 581 582 583 Patient Information 584 IMITREX® (IM-i-trex) 585 (sumatriptan succinate) 586 Injection 587 588 Read this Patient Information before you start taking IMITREX and each time you get a refill. 589 There may be new information. This information does not take the place of talking with your 590 healthcare provider about your medical condition or treatment. 591 592 What is the most important information I should know about IMITREX? 593 IMITREX can cause serious side effects, including: 594 Heart attack and other heart problems. Heart problems may lead to death. 595 Stop taking IMITREX and get emergency medical help right away if you have any of the 596 following symptoms of a heart attack: 597  discomfort in the center of your chest that lasts for more than a few minutes, or that goes 598 away and comes back 599  severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw 600  pain or discomfort in your arms, back, neck, jaw, or stomach 601  shortness of breath with or without chest discomfort 19 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 602  breaking out in a cold sweat 603  nausea or vomiting 604  feeling lightheaded 605 IMITREX is not for people with risk factors for heart disease unless a heart exam is done and 606 shows no problem. You have a higher risk for heart disease if you: 607  have high blood pressure 608  have high cholesterol levels 609  smoke 610  are overweight 611  have diabetes 612  have a family history of heart disease 613 614 What is IMITREX? 615 IMITREX is a prescription medicine used to treat acute migraine headaches with or without aura 616 and acute cluster headaches in adults who have been diagnosed with migraine or cluster 617 headaches. 618 IMITREX is not used to treat other types of headaches such as hemiplegic (that make you unable 619 to move on one side of your body) or basilar (rare form of migraine with aura) migraines. IMITREX is not used to prevent or decrease the number of migraine or cluster headaches you have. 620 It is not known if IMITREX is safe and effective in children under 18 years of age. 621 622 Who should not take IMITREX? 623 Do not take IMITREX if you have: 624  heart problems or a history of heart problems 625  narrowing of blood vessels to your legs, arms, stomach, or kidney (peripheral vascular 626 disease) 627  uncontrolled high blood pressure 628  hemiplegic migraines or basilar migraines. If you are not sure if you have these types of 629 migraines, ask your healthcare provider. 630  had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation 631  taken any of the following medicines in the last 24 hours: 632  almotriptan (AXERT®) 633  eletriptan (RELPAX®) 634  frovatriptan (FROVA®) 635  naratriptan (AMERGE®) 636  rizatriptan (MAXALT®, MAXALT-MLT®) 637  sumatriptan and naproxen (TREXIMET®) 20 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 638  ergotamines (CAFERGOT®, ERGOMAR®, MIGERGOT®) 639  dihydroergotamine (D.H.E. 45®, MIGRANAL®) 640 Ask your healthcare provider if you are not sure if your medicine is listed above. 641  an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of this leaflet for 642 a complete list of ingredients in IMITREX. 643 644 What should I tell my healthcare provider before taking IMITREX? 645 Before you take IMITREX, tell your healthcare provider about all of your medical conditions, 646 including if you: 647  have high blood pressure 648  have high cholesterol 649  have diabetes 650  smoke 651  are overweight 652  have heart problems or family history of heart problems or stroke 653  have liver problems 654  have had epilepsy or seizures 655  are not using effective birth control 656  become pregnant while taking IMITREX 657  are breastfeeding or plan to breastfeed. IMITREX passes into your breast milk and may harm 658 your baby. Talk with your healthcare provider about the best way to feed your baby if you 659 take IMITREX. 660 Tell your healthcare provider about all the medicines you take, including prescription and 661 nonprescription medicines, vitamins, and herbal supplements. 662 Using IMITREX with certain other medicines can affect each other, causing serious side effects. 663 Especially tell your healthcare provider if you take anti-depressant medicines called: 664  selective serotonin reuptake inhibitors (SSRIs) 665  serotonin norepinephrine reuptake inhibitors (SNRIs) 666  tricyclic antidepressants (TCAs) 667  monoamine oxidase inhibitors (MAOIs) 668 Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. 669 Know the medicines you take. Keep a list of them to show your healthcare provider or 670 pharmacist when you get a new medicine. 671 672 How should I take IMITREX? 21 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 673  Certain people should take their first dose of IMITREX in their healthcare provider’s office 674 or in another medical setting. Ask your healthcare provider if you should take your first dose 675 in a medical setting. 676  Use IMITREX exactly as your healthcare provider tells you to use it. 677  Your healthcare provider may change your dose. Do not change your dose without first 678 talking with your healthcare provider. 679  For adults, the usual dose is a single injection given just below the skin. 680  You should give an injection as soon as the symptoms of your headache start, but it may be 681 given at any time during a migraine attack. 682  If you did not get any relief after the first injection, do not give a second injection without 683 first talking with your healthcare provider. 684  You can take a second injection 1 hour after the first injection, but not sooner, if your 685 headache came back after your first injection. 686  Do not take more than 12 mg in a 24-hour period. 687  If you use too much IMITREX, call your healthcare provider or go to the nearest hospital 688 emergency room right away. 689  You should write down when you have headaches and when you take IMITREX so you can 690 talk with your healthcare provider about how IMITREX is working for you. 691 692 What should I avoid while taking IMITREX? 693 IMITREX can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not 694 drive a car, use machinery, or do anything where you need to be alert. 695 696 What are the possible side effects of IMITREX? 697 IMITREX may cause serious side effects. See “What is the most important information I 698 should know about IMITREX?” 699 These serious side effects include: 700  changes in color or sensation in your fingers and toes (Raynaud’s syndrome) 701  stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of 702 gastrointestinal and colonic ischemic events include: 703  sudden or severe stomach pain 704  stomach pain after meals 705  weight loss 706  nausea or vomiting 707  constipation or diarrhea 708  bloody diarrhea 709  fever 710  problems with blood circulation to your legs and feet (peripheral vascular ischemia). 711 Symptoms of peripheral vascular ischemia include: 22 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 712  cramping and pain in your legs or hips 713  feeling of heaviness or tightness in your leg muscles 714  burning or aching pain in your feet or toes while resting 715  numbness, tingling, or weakness in your legs 716  cold feeling or color changes in 1 or both legs or feet 717  medication overuse headaches. Some people who use too many IMITREX injections may 718 have worse headaches (medication overuse headache). If your headaches get worse, your 719 healthcare provider may decide to stop your treatment with IMITREX. 720  serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in 721 people using IMITREX, especially if IMITREX is used with anti-depressant medicines 722 called SSRIs or SNRIs. 723 Call your healthcare provider right away if you have any of the following symptoms of 724 serotonin syndrome: 725  mental changes such as seeing things that are not there (hallucinations), agitation, or 726 coma 727  fast heartbeat 728  changes in blood pressure 729  high body temperature 730  tight muscles 731  trouble walking 732  seizures. Seizures have happened in people taking IMITREX who have never had seizures 733 before. Talk with your healthcare provider about your chance of having seizures while you 734 take IMITREX. 735 The most common side effects of IMITREX include: 736  pain or redness at your injection site 737  tingling or numbness in your fingers or toes 738  dizziness 739  warm, hot, burning feeling to your face (flushing) 740  discomfort or stiffness in your neck 741  feeling weak, drowsy, or tired 742 Tell your healthcare provider if you have any side effect that bothers you or that does not go 743 away. 744 These are not all the possible side effects of IMITREX. For more information, ask your 745 healthcare provider or pharmacist. 746 Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 747 800-FDA-1088. 748 23 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c o mpany logo 749 How should I store IMITREX Injection? 750  Store IMITREX between 36°F to 86°F (2°C to 30°C). 751  Store your medicine away from light. 752  Keep your medicine in the packaging or carrying case provided with it. 753 Keep IMITREX and all medicines out of the reach of children. 754 755 General information about the safe and effective use of IMITREX 756 Medicines are sometimes prescribed for purposes other than those listed in Patient Information 757 leaflets. Do not use IMITREX for a condition for which it was not prescribed. Do not give 758 IMITREX to other people, even if they have the same symptoms you have. It may harm them. 759 This Patient Information leaflet summarizes the most important information about IMITREX. If 760 you would like more information, talk with your healthcare provider. You can ask your 761 healthcare provider or pharmacist for information about IMITREX that is written for healthcare 762 professionals. 763 For more information, go to www.gsk.com or call 1-888-825-5249. 764 765 What are the ingredients in IMITREX Injection? 766 Active ingredient: sumatriptan succinate 767 Inactive ingredients: sodium chloride, water for injection 768 769 This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug 770 Administration. 771 772 IMITREX, AMERGE, TREXIMET are registered trademarks of GlaxoSmithKline. The other 773 brands listed are trademarks of their respective owners and are not trademarks of 774 GlaxoSmithKline. The makers of these brands are not affiliated with and do not endorse 775 GlaxoSmithKline or its products. 776 781 782 ©2012, GlaxoSmithKline. All rights reserved. 783 784 September 2012 785 24 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 10 35 15 20 25 30 1 Patient Information 2 IMITREX® (IM-i-trex) 3 (sumatriptan succinate) 4 Injection 6 Read this Patient Information before you start taking IMITREX and each time you 7 get a refill. There may be new information. This information does not take the place 8 of talking with your healthcare provider about your medical condition or treatment. 9 What is the most important information I should know about IMITREX? 11 IMITREX can cause serious side effects, including: 12 Heart attack and other heart problems. Heart problems may lead to death. 13 Stop taking IMITREX and get emergency medical help right away if you 14 have any of the following symptoms of a heart attack:  discomfort in the center of your chest that lasts for more than a few minutes, or 16 that goes away and comes back 17  severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw 18  pain or discomfort in your arms, back, neck, jaw, or stomach 19  shortness of breath with or without chest discomfort  breaking out in a cold sweat 21  nausea or vomiting 22  feeling lightheaded 23 IMITREX is not for people with risk factors for heart disease unless a heart exam is 24 done and shows no problem. You have a higher risk for heart disease if you:  have high blood pressure 26  have high cholesterol levels 27  smoke 28  are overweight 29  have diabetes  have a family history of heart disease 31 32 What is IMITREX? 33 IMITREX is a prescription medicine used to treat acute migraine headaches with or 34 without aura and acute cluster headaches in adults who have been diagnosed with migraine or cluster headaches. 36 IMITREX is not used to treat other types of headaches such as hemiplegic (that 37 make you unable to move on one side of your body) or basilar (rare form of 38 migraine with aura) migraines. 1 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMITREX is not used to prevent or decrease the number of migraine or cluster headaches you have. 39 It is not known if IMITREX is safe and effective in children under 18 years of age. 40 41 Who should not take IMITREX? 42 Do not take IMITREX if you have: 43  heart problems or a history of heart problems 44  narrowing of blood vessels to your legs, arms, stomach, or kidney (peripheral 45 vascular disease) 46  uncontrolled high blood pressure 47  hemiplegic migraines or basilar migraines. If you are not sure if you have these 48 types of migraines, ask your healthcare provider. 49  had a stroke, transient ischemic attacks (TIAs), or problems with your blood 50 circulation 51  taken any of the following medicines in the last 24 hours: 52  almotriptan (AXERT®) 53  eletriptan (RELPAX®) 54  frovatriptan (FROVA®) 55  naratriptan (AMERGE®) 56  rizatriptan (MAXALT®, MAXALT-MLT®) 57  sumatriptan and naproxen (TREXIMET®) 58  ergotamines (CAFERGOT®, ERGOMAR®, MIGERGOT®) 59  dihydroergotamine (D.H.E. 45®, MIGRANAL®) 60 Ask your healthcare provider if you are not sure if your medicine is listed above. 61  an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of 62 this leaflet for a complete list of ingredients in IMITREX. 63 64 What should I tell my healthcare provider before taking IMITREX? 65 Before you take IMITREX, tell your healthcare provider about all of your medical 66 conditions, including if you: 67  have high blood pressure 68  have high cholesterol 69  have diabetes 70  smoke 71  are overweight 72  have heart problems or family history of heart problems or stroke 73  have liver problems 74  have had epilepsy or seizures 75  are not using effective birth control 2 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 76  become pregnant while taking IMITREX 77  are breastfeeding or plan to breastfeed. IMITREX passes into your breast milk 78 and may harm your baby. Talk with your healthcare provider about the best way 79 to feed your baby if you take IMITREX. 80 Tell your healthcare provider about all the medicines you take, including 81 prescription and nonprescription medicines, vitamins, and herbal supplements. 82 Using IMITREX with certain other medicines can affect each other, causing serious 83 side effects. 84 Especially tell your healthcare provider if you take anti-depressant medicines 85 called: 86  selective serotonin reuptake inhibitors (SSRIs) 87  serotonin norepinephrine reuptake inhibitors (SNRIs) 88  tricyclic antidepressants (TCAs) 89  monoamine oxidase inhibitors (MAOIs) 90 Ask your healthcare provider or pharmacist for a list of these medicines if you are 91 not sure. 92 Know the medicines you take. Keep a list of them to show your healthcare provider 93 or pharmacist when you get a new medicine. 94 95 How should I take IMITREX? 96  Certain people should take their first dose of IMITREX in their healthcare 97 provider’s office or in another medical setting. Ask your healthcare provider if 98 you should take your first dose in a medical setting. 99  Use IMITREX exactly as your healthcare provider tells you to use it. 100  Your healthcare provider may change your dose. Do not change your dose 101 without first talking with your healthcare provider. 102  For adults, the usual dose is a single injection given just below the skin. 103  You should give an injection as soon as the symptoms of your headache start, 104 but it may be given at any time during a migraine attack. 105  If you did not get any relief after the first injection, do not give a second 106 injection without first talking with your healthcare provider. 107  You can take a second injection 1 hour after the first injection, but not sooner, if 108 your headache came back after your first injection. 109  Do not take more than 12 mg in a 24-hour period. 110  If you use too much IMITREX, call your healthcare provider or go to the nearest 111 hospital emergency room right away. 3 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 112  You should write down when you have headaches and when you take IMITREX 113 so you can talk with your healthcare provider about how IMITREX is working for 114 you. 115 116 What should I avoid while taking IMITREX? 117 IMITREX can cause dizziness, weakness, or drowsiness. If you have these 118 symptoms, do not drive a car, use machinery, or do anything where you need to be 119 alert. 120 121 What are the possible side effects of IMITREX? 122 IMITREX may cause serious side effects. See “What is the most important 123 information I should know about IMITREX?” 124 These serious side effects include: 125  changes in color or sensation in your fingers and toes (Raynaud’s syndrome) 126  stomach and intestinal problems (gastrointestinal and colonic ischemic events). 127 Symptoms of gastrointestinal and colonic ischemic events include: 128  sudden or severe stomach pain 129  stomach pain after meals 130  weight loss 131  nausea or vomiting 132  constipation or diarrhea 133  bloody diarrhea 134  fever 135  problems with blood circulation to your legs and feet (peripheral vascular 136 ischemia). Symptoms of peripheral vascular ischemia include: 137  cramping and pain in your legs or hips 138  feeling of heaviness or tightness in your leg muscles 139  burning or aching pain in your feet or toes while resting 140  numbness, tingling, or weakness in your legs 141  cold feeling or color changes in 1 or both legs or feet 142  medication overuse headaches. Some people who use too many IMITREX 143 injections may have worse headaches (medication overuse headache). If your 144 headaches get worse, your healthcare provider may decide to stop your treatment with IMITREX. 146  serotonin syndrome. Serotonin syndrome is a rare but serious problem that can 147 145 happen in people using IMITREX, especially if IMITREX is used with anti-depressant medicines called SSRIs or SNRIs. 148 Call your healthcare provider right away if you have any of the following 149 symptoms of serotonin syndrome: 150 4 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 151  mental changes such as seeing things that are not there (hallucinations), agitation, or coma 153  fast heartbeat 154  changes in blood pressure 155  high body temperature 156  tight muscles 157  trouble walking 158  seizures. Seizures have happened in people taking IMITREX who have never had 159 seizures before. Talk with your healthcare provider about your chance of having 160 seizures while you take IMITREX. 152 161 The most common side effects of IMITREX include: 162  pain or redness at your injection site 163  tingling or numbness in your fingers or toes 164  dizziness 165  warm, hot, burning feeling to your face (flushing) 166  discomfort or stiffness in your neck 167  feeling weak, drowsy, or tired 168 Tell your healthcare provider if you have any side effect that bothers you or that 169 does not go away. 170 These are not all the possible side effects of IMITREX. For more information, ask 171 your healthcare provider or pharmacist. 172 Call your doctor for medical advice about side effects. You may report side effects 173 to FDA at 1-800-FDA-1088. 174 175 How should I store IMITREX Injection? 176  Store IMITREX between 36°F to 86°F (2°C to 30°C). 177  Store your medicine away from light. 178  Keep your medicine in the packaging or carrying case provided with it. 179 Keep IMITREX and all medicines out of the reach of children. 180 181 General information about the safe and effective use of IMITREX 182 Medicines are sometimes prescribed for purposes other than those listed in Patient 183 Information leaflets. Do not use IMITREX for a condition for which it was not 184 prescribed. Do not give IMITREX to other people, even if they have the same 185 symptoms you have. It may harm them. 186 This Patient Information leaflet summarizes the most important information about 187 IMITREX. If you would like more information, talk with your healthcare provider. 5 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda u s a g e illustration 188 You can ask your healthcare provider or pharmacist for information about IMITREX 189 that is written for healthcare professionals. 190 For more information, go to www.gsk.com or call 1-888-825-5249. 191 192 What are the ingredients in IMITREX Injection? 193 Active ingredient: sumatriptan succinate 194 Inactive ingredients: sodium chloride, water for injection 195 196 Month Year 197 IMJ:xPPI 198 199 200 201 202 203 Read this Patient Instructions for Use before you start to use the IMITREX STATdose System. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about IMITREX Injection when you start taking it and at regular checkups. 204 Keep the IMITREX STATdose System out of the reach of children. 205 Before you use the IMITREX STATdose System 206 207 When you first open the IMITREX STATdose System box, the Cartridge Pack and the IMITREX STATdose Pen® are already in the Carrying Case for your convenience. 209 210 211 The grey and blue Carrying Case is used for storing the unloaded Pen and the Cartridge Pack when they are not being used. 212 213 214 215 216 The Cartridge Pack holds 2 individually sealed Syringe Cartridges. Each Syringe Cartridge holds 1 dose of IMITREX® (sumatriptan succinate) Injection. The Cartridge Pack for the 4-mg strength of this 208 6 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration 217 medicine is yellow, and the Cartridge Pack for the 6-mg strength is blue (as shown). Refill 218 Cartridge Packs are available. 219 220 The grey and blue Pen is used to automatically inject 1 dose of medicine from a 221 Syringe Cartridge. Do not touch the Blue Button until you have pressed the Pen 222 against your skin to give a dose. If you press it at any other time, you might lose a 223 dose. The Safety Catch keeps the Pen from accidentally firing until you are ready. 224 The Pen will only work when you slide the grey part of the barrel down to the blue 225 part. Always check to make sure that the white Priming Rod is not sticking out from 226 the end of the Pen (as shown in Figure B) before you load a new Syringe Cartridge. 227 If it is sticking out, you will lose that dose. 228 How to load the IMITREX STATdose Pen 229 Do not load the Pen until you are ready to give yourself an injection. 230 Do not touch the Blue Button on top of the Pen (see Figure A) 231 while you are loading the Pen. 232 240 1. Open the lid of the Carrying Case. The tamper 241 evident seals over the 2 Syringe Cartridges are 242 labeled “A” and “B” (see Figure A inset). 243 Always use the Syringe Cartridge marked “A” 244 before the one marked “B” to help you keep 245 track of your doses. Do not use if either 246 seal is broken or missing when you first 233 247 open the Carrying Case. 234 235 248 2. Tear off one of the tamper-evident seals (see 249 Figure A). Throw away the seal. Open the lid 236 250 over the Syringe Cartridge. 251 3. Hold the Pen by the ridges at the top. Take 252 the Pen out of the Carrying Case (see Figure 253 B). 254 Check to make sure the white Priming Rod is 255 not sticking out from the lower end of the Pen 256 (see Figure B inset). If it is sticking out, put 257 the Pen back into the Carrying Case and press 237 238 258 down firmly until you feel it click. Take the 239 259 Pen out of the Carrying Case. usage illustration Figure A Figure B 7 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 264 4. Put the Pen in the Cartridge Pack. Turn it to 265 the right (clockwise) until it will not turn any 266 more (about half a turn) (see Figure C). 267 268 269 270 271 261 Figure C 272 5. Hold the loaded Pen by the ridges and pull it 273 straight out (see Figure D). You may need 274 to pull hard on the Pen, but this is normal. Do 275 not press the Blue Button yet. 262 263 276 The Pen is now ready to use. Do not put the loaded Pen back into the Carrying 277 Case because that will damage the needle. usage illustrationusage illustration Figure D 278 How to use the IMITREX STATdose Pen to take your medicine 279 Before injecting your medicine, choose an area with a fatty tissue layer (see Figure 280 E or Figure F). Ask your healthcare provider if you have a question about where to 281 inject your medicine. 282 To prepare the area of skin where IMITREX is to be injected, wipe the injection site 283 with an alcohol swab. Do not touch this area again before giving the injection. 284 usag e il lustration 288 Figure E or Figure F Figure G 289 6. Without pushing the Blue Button, press the loaded Pen firmly against the skin 290 so that the grey barrel slides down toward the blue section that holds the 8 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration 291 Syringe Cartridge (see Figure D). (This releases the Safety Catch that keeps the Pen from firing by mistake until you are ready.) 293 7. Push the Blue Button. Hold the Pen still for at least 5 seconds. If the Pen is 294 292 taken away from the skin too soon, not all the medicine will come out. 295 8. After 5 seconds, carefully take the Pen away from your skin. The needle will 296 be showing (see Figure G). Do not touch the needle. 297 How to unload the IMITREX STATdose Pen after taking your medicine 298 Right after you take a dose with the Pen, you need to return the used Syringe 299 Cartridge to the Cartridge Pack. usage illustrationusage illustration Figure J 300 302 301 Figure H 303 Figure I 304 305 306 9. Push the Pen down into the empty side of the Cartridge Pack as far as it will go 307 (see Figure H). 308 10. Turn the Pen to the left (counterclockwise) about half a turn until it is released 309 from the Syringe Cartridge (see Figure I). 310 11. Pull the empty Pen out of the Cartridge Pack (see Figure J). 311 Because the Pen has now been used, the white Priming Rod will stick out from 312 the lower end of the Pen (see Figure J). 313 12. Close the Cartridge Pack lid over the used Syringe Cartridge. When the used 314 Syringe Cartridges are inserted correctly, the Cartridge Pack is a disposable, 315 protective case to help you avoid needle sticks and use the syringes correctly. 316 13. Put the Pen back into the Carrying Case and press it down firmly until you feel 317 it click. Close the Carrying Case lid. This gets the Pen ready for the next use. If the lid will not close, push the Pen down until you feel it click. Then close the 319 lid. 318 9 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration 320 How to take out a used Cartridge Pack 321 After both Syringe Cartridges have been used, take the Cartridge Pack out of the 322 Carrying Case. Never reuse or recycle a Syringe Cartridge. usage illustrationusage illustration Figure L 323 325 324 Figure K 326 327 14. Open the Carrying Case lid. 328 15. Hold the Carrying Case with one hand and press the 2 buttons on either side of 329 the Carrying Case (see Figure K). 330 16. Gently pull out the Cartridge Pack with the other hand (see Figure L). 331 17. Throw away the Cartridge Pack or dispose of it as instructed by your healthcare 332 provider. There may be special state and local laws for disposing of used 333 needles and syringes. Always keep out of the reach of children. 334 How to insert a new Cartridge Pack 335 usage illustrationusage illustration Figure O 336 340 338 337 339 Figure N 341 342 17. Take the new Cartridge Pack out of its box. Do not take off the 343 tamper-evident seals (see Figure M). 344 18. Put the Cartridge Pack in the Carrying Case. Slide it down smoothly (see 345 Figure N). 346 19. The Cartridge Pack will click into place when the 2 buttons show through the 347 holes in the Carrying Case (see Figure O). Close the lid. 348 Figure M 10 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 349 This Patient Information and Instructions for Use has been approved by the U.S. 350 Food and Drug Administration. 351 352 AMERGE, IMITREX, IMITREX STATdose System, IMITREX STATdose Pen, and 353 TREXIMET are registered trademarks of GlaxoSmithKline. The other brands listed 354 are trademarks of their respective owners and are not trademarks of 355 GlaxoSmithKline. The makers of these brands are not affiliated with and do not 356 endorse GlaxoSmithKline or its products. 357 comp any logo 360 GlaxoSmithKline 361 Research Triangle Park, NC 27709 362 363 ©2012, GlaxoSmithKline. All rights reserved. 364 365 Month Year 366 IMJ:xPIL 11 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:41.244424	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020080s039s040s041s045lbl.pdf', 'application_number': 20080, 'submission_type': 'SUPPL ', 'submission_number': 41}
12,187	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IMITREX safely and effectively. See full prescribing information for IMITREX. IMITREX (sumatriptan succinate) injection, for subcutaneous use Initial U.S. Approval: 1992 ----------------------------INDICATIONS AND USAGE-------------------- IMITREX is a serotonin (5-HT1B/1D) receptor agonist (triptan) indicated for:  Acute treatment of migraine with or without aura in adults (1)  Acute treatment of cluster headache in adults (1) Limitations of Use:  Use only if a clear diagnosis of migraine or cluster headache has been established. (1)  Not indicated for the prevention of migraine attacks. (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------  For subcutaneous use only. (2.1)  Acute treatment of migraine: 1- to 6-mg Single dose. (2.1)  Acute treatment of cluster headache: 6-mg Single dose. (2.1)  Maximum dose in a 24-hour period: 12 mg, Separate doses by at least 1 hour. (2.1)  Patients receiving doses other than 4 or 6 mg: Use the 6-mg single-dose vial. (2.3) ---------------------DOSAGE FORMS AND STRENGTHS -------------  Injection: 4- and 6-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose Pen (3)  Injection: 6-mg single-dose vial (3) -------------------------------CONTRAINDICATIONS-----------------------  Coronary artery disease or coronary vasospasm (4)  Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders (4)  History of stroke, transient ischemic attack, or hemiplegic or basilar migraine (4)  Peripheral vascular disease (4)  Ischemic bowel disease (4)  Uncontrolled hypertension (4)  Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another triptan) or of an ergotamine-containing medication (4)  Ccurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor (4)  Known hypersensitivity to sumatriptan (4)  Severe hepatic impairment (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------  Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. (5.1)  Arrhythmias: Discontinue IMITREX if occurs. (5.2)  Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. (5.3)  Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue IMITREX if occurs. (5.4)  Gastrointestinal ischemia and infarction events, peripheral vasospastic reactions: Discontinue IMITREX if occurs. (5.5)  Medication overuse headache: Detoxification may be necessary. (5.6)  Serotonin syndrome: Discontinue IMITREX if occurs. (5.7)  Increase in blood pressure: Monitor blood pressure. (5.8)  Anaphylactic/anaphylactoid reactions: Discontinue IMITREX if occurs (5.9)  Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. (5.10) ------------------------------ ADVERSE REACTIONS ---------------------- Most common adverse reactions (5% and > placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------- USE IN SPECIFIC POPULATIONS ---------------  Pregnancy: Based on animal data, may cause fetal harm (8.1)  Geriatric use: A cardiovascular evaluation is recommended in those who have other cardiovascular risk factors prior to receiving IMITREX. (8.5) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 09/2012 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Administration Using the IMITREX STATdose Pen ® 2.3 Administration of Doses of IMITREX Other Than 4 or 6 mg 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina 5.2 Arrhythmias 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 5.4 Cerebrovascular Events 5.5 Other Vasospasm Reactions 5.6 Medication Overuse Headache 5.7 Serotonin Syndrome 5.8 Increase in Blood Pressure 5.9 Anaphylactic/Anaphylactoid Reactions 5.10 Seizures 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Ergot-Containing Drugs 7.2 Monoamine Oxidase-A Inhibitors 7.3 Other 5-HT1 Agonists 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Migraine 14.2 Cluster Headache 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events 17.2 Anaphylactic/Anaphylactoid Reactions 17.3 Medication Overuse Headache 17.4 Pregnancy 17.5 Nursing Mothers 17.6 Ability To Perform Complex Tasks 1 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 10 15 20 25 30 35 17.7 Serotonin Syndrome *Sections or subsections omitted from the full prescribing information are not 17.8 How to Use IMITREX Injection listed. 1 FULL PRESCRIBING INFORMATION 2 1 INDICATIONS AND USAGE 3 IMITREX® Injection is indicated in adults for (1) the acute treatment of migraine, with or 4 without aura, and (2) the acute treatment of cluster headache. Limitations of Use: 6  Use only if a clear diagnosis of migraine or cluster headache has been established. 7  If a patient has no response to the first migraine attack treated with IMITREX, reconsider the 8 diagnosis of migraine before IMITREX is administered to treat any subsequent attacks. 9  IMITREX is not indicated for the prevention of migraine attacks. 2 DOSAGE AND ADMINISTRATION 11 2.1 Dosing Information 12 The maximum single recommended adult dose of IMITREX Injection for the acute 13 treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of 14 migraine, if side effects are dose limiting, lower doses (1 to 5 mg) may be used [see Clinical Studies (14.1)]. For the treatment of cluster headache, the efficacy of lower doses has not been 16 established. 17 The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg 18 injections separated by at least 1 hour. A second 6-mg dose should only be considered if some 19 response to a first injection was observed. 2.2 Administration Using the IMITREX STATdose Pen® 21 An autoinjector device (IMITREX STATdose Pen) is available for use with 4- and 6-mg 22 prefilled syringe cartridges. With this device, the needle penetrates approximately 1/4 inch (5 to 23 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular 24 delivery must be avoided. Instruct patients on the proper use of IMITREX STATdose Pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to 26 accommodate the length of the needle. 27 2.3 Administration of Doses of IMITREX Other Than 4 or 6 mg 28 In patients receiving doses other than 4 or 6 mg, use the 6-mg single-dose vial; do not use 29 the IMITREX STATdose Pen. Visually inspect the vial for particulate matter and discoloration before administration. Do not use if particulates and discolorations are noted. 31 3 DOSAGE FORMS AND STRENGTHS 32  Injection: 4- and 6-mg single-dose prefilled syringe cartridges for use with the IMITREX 33 STATdose Pen 34  Injection: 6-mg single-dose vial 4 CONTRAINDICATIONS 36 IMITREX Injection is contraindicated in patients with: 2 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 37  Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or 38 documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina 39 [see Warnings and Precautions (5.1)]. 40  Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory 41 conduction pathway disorders [see Warnings and Precautions (5.2)]. 42  History of stroke or transient ischemic attack (TIA) because these patients are at a higher risk 43 of stroke [see Warnings and Precautions (5.4)]. 44  History of hemiplegic or basilar migraine. 45  Peripheral vascular disease [see Warnings and Precautions (5.5)]. 46  Ischemic bowel disease [see Warnings and Precautions (5.5)]. 47  Uncontrolled hypertension [see Warnings and Precautions (5.8)]. 48  Recent (i.e., within 24 hours) use of ergotamine-containing medication, ergot-type 49 medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 50 (5-HT1) agonist [see Drug Interactions (7.1, 7.3)]. 51  Concurrent administration of an MAO-A inhibitor or recent (within 2 weeks) use of an 52 MAO-A inhibitor [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 53  Known hypersensitivity to sumatriptan [see Warnings and Precautions (5.9) and Adverse 54 Reactions (6.2)]. 55  Severe hepatic impairment [see Clinical Pharmacology (12.3)]. 56 5 WARNINGS AND PRECAUTIONS 57 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina 58 The use of IMITREX Injection is contraindicated in patients with ischemic or vasospastic 59 CAD. There have been rare reports of serious cardiac adverse reactions, including acute 60 myocardial infarction, occurring within a few hours following administration of IMITREX 61 Injection. Some of these reactions occurred in patients without known CAD. 5-HT1 agonists, 62 including IMITREX Injection, may cause coronary artery vasospasm (Prinzmetal’s angina), even 63 in patients without a history of CAD. 64 Perform a cardiovascular evaluation in triptan-naive patients who have multiple 65 cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong 66 family history of CAD) prior to receiving IMITREX Injection. If there is evidence of CAD or 67 coronary artery vasospasm, IMITREX Injection is contraindicated. For patients with multiple 68 cardiovascular risk factors who have a negative cardiovascular evaluation, consider 69 administering the first dose of IMITREX Injection in a medically supervised setting and 70 performing an electrocardiogram (ECG) immediately following IMITREX Injection. For such 71 patients, consider periodic cardiovascular evaluation in intermittent long-term users of IMITREX 72 Injection. 73 Evaluate patients with signs or symptoms suggestive of angina following IMITREX 74 Injection for the presence of CAD or Prinzmetal’s angina before receiving additional doses of 75 IMITREX Injection. Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 76 5.2 Arrhythmias 77 Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and 78 ventricular fibrillation leading to death, have been reported within a few hours following the 79 administration of 5-HT1 agonists. Discontinue IMITREX Injection if these disturbances occur. 80 IMITREX Injection is contraindicated in patients with Wolff-Parkinson-White syndrome or 81 arrhythmias associated with other cardiac accessory conduction pathway disorders 82 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 83 As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the 84 precordium, throat, neck, and jaw commonly occur after treatment with IMITREX Injection and 85 are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at 86 high cardiac risk. The use of IMITREX Injection is contraindicated in patients shown to have 87 CAD and those with Prinzmetal’s variant angina. 88 5.4 Cerebrovascular Events 89 Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients 90 treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears 91 possible that the cerebrovascular events were primary, the 5-HT1 agonist having been 92 administered in the incorrect belief that the symptoms experienced were a consequence of 93 migraine when they were not. Also, patients with migraine may be at increased risk of certain 94 cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue IMITREX Injection if a 95 cerebrovascular event occurs. 96 As with other acute migraine therapies, before treating headaches in patients not 97 previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, 98 exclude other potentially serious neurological conditions. IMITREX Injection is contraindicated 99 in patients with a history of stroke or TIA. 100 5.5 Other Vasospasm Reactions 101 5-HT1 agonists, including IMITREX Injection, may cause non-coronary vasospastic 102 reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction 103 (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s 104 syndrome. Until further evaluation, IMITREX Injection is contraindicated in patients who 105 experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use 106 of any 5-HT1 agonist. 107 Reports of transient and permanent blindness and significant partial vision loss have been 108 reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, 109 a causal relationship between these events and the use of 5-HT1 agonists have not been clearly 110 established. 111 5.6 Medication Overuse Headache 112 Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, combination of 113 drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse 114 headache). Medication overuse headache may present as migraine-like daily headaches, or as a 115 marked increase in frequency of migraine attacks. Detoxification of patients, including 4 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 116 withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes 117 a transient worsening of headache) may be necessary. 118 5.7 Serotonin Syndrome 119 Serotonin syndrome may occur with triptans, including IMITREX Injection, particularly 120 during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin 121 norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO 122 inhibitors [see Drug Interactions (7.4)]. Serotonin syndrome symptoms may include mental 123 status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, 124 labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, 125 incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of 126 symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a 127 serotonergic medication. Discontinue IMITREX Injection if serotonin syndrome is suspected. 128 5.8 Increase in Blood Pressure 129 Significant elevation in blood pressure, including hypertensive crisis with acute 130 impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 131 agonists, including patients without a history of hypertension. Monitor blood pressure in patients 132 treated with IMITREX. IMITREX Injection is contraindicated in patients with uncontrolled 133 hypertension. 134 5.9 Anaphylactic/Anaphylactoid Reactions 135 Anaphylactic/anaphylactoid reactions have occurred in patients receiving sumatriptan. 136 Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are 137 more likely to occur in individuals with a history of sensitivity to multiple allergens. IMITREX 138 Injection is contraindicated in patients with prior serious anaphylactic reaction. 139 5.10 Seizures 140 Seizures have been reported following administration of sumatriptan. Some have 141 occurred in patients with either a history of seizures or concurrent conditions predisposing to 142 seizures. There are also reports in patients where no such predisposing factors are apparent. 143 IMITREX Injection should be used with caution in patients with a history of epilepsy or 144 conditions associated with a lowered seizure threshold. 145 6 ADVERSE REACTIONS 146 The following adverse reactions are discussed in more detail in other sections of the 147 labeling: 148  Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina [see Warnings and 149 Precautions (5.1)] 150  Arrhythmias [see Warnings and Precautions (5.2)] 151  Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)] 152  Cerebrovascular events [see Warnings and Precautions (5.4)] 153  Other vasospasm reactions [see Warnings and Precautions (5.5)] 154  Medication overuse headache [see Warnings and Precautions (5.6)] Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 155  Serotonin syndrome [see Warnings and Precautions (5.7)] 156  Increase in blood pressure [see Warnings and Precautions (5.8)] 157  Anaphylactic/anaphylactoid reactions [see Warnings and Precautions (5.9)] 158  Seizures [see Warnings and Precautions (5.10)] 159 6.1 Clinical Trials Experience 160 Because clinical trials are conducted under widely varying conditions, adverse reaction 161 rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical 162 trials of another drug and may not reflect the rates observed in practice. 163 Migraine Headache: Table 1 lists adverse reactions that occurred in 2 US 164 placebo-controlled clinical trials in migraine subjects [Studies 2 and 3, see Clinical Studies 165 (14.1)] following either a single 6-mg dose of IMITREX Injection or placebo. Only reactions 166 that occurred at a frequency of 2% or more in groups treated with IMITREX Injection 6 mg and 167 that occurred at a frequency greater than the placebo group are included in Table 1. 168 169 Table 1. Adverse Reactions Reported by at Least 2% of Subjects and at a Greater 170 Frequency Than Placebo in 2 Placebo-Controlled Migraine Clinical Trials (Studies 2 171 and 3)a Adverse Reaction Percent of Subjects Reporting IMITREX Injection 6 mg Subcutaneous (n = 547) Placebo (n = 370) Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort Tightness in chest Pressure in chest 5 3 2 1 <1 <1 Ear, nose, and throat Throat discomfort Discomfort: nasal cavity/sinuses 3 2 <1 <1 Injection site reactionb 59 24 6 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness Neck pain/stiffness Myalgia 5 5 2 <1 <1 <1 Neurological Dizziness/vertigo Drowsiness/sedation Headache 12 3 2 4 2 <1 Skin Sweating 2 1 172 a The sum of the percentages cited is greater than 100% because subjects may have 173 experienced more than 1 type of adverse reaction. Only reactions that occurred at a 174 frequency of 2% or more in groups treated with IMITREX Injection and occurred at a 175 frequency greater than the placebo groups are included. 176 b Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding. 177 178 The incidence of adverse reactions in controlled clinical trials was not affected by gender 179 or age of the subjects. There were insufficient data to assess the impact of race on the incidence 180 of adverse reactions. 181 Cluster Headache: In the controlled clinical trials assessing the efficacy of IMITREX 182 Injection as a treatment for cluster headache [Studies 4 and 5, see Clinical Studies (14.2)], no 183 new significant adverse reactions were detected that had not already been identified in trials of 184 IMITREX in subjects with migraine. 185 Overall, the frequency of adverse reactions reported in the trials of cluster headache was 186 generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% 187 IMITREX, 0% placebo), nausea and vomiting (4% IMITREX, 0% placebo), and bronchospasm 188 (1% IMITREX, 0% placebo). 189 Other Adverse Reactions: In the paragraphs that follow, the frequencies of less 190 commonly reported adverse reactions are presented. Reaction frequencies were calculated as the 191 number of subjects reporting a reaction divided by the total number of subjects (N = 6,218) 192 exposed to subcutaneous IMITREX Injection. All reported reactions are included except those 193 already listed in the previous table. Reactions are further classified within body system 194 categories and enumerated in order of decreasing frequency using the following definitions: 195 frequent are defined as those occurring in at least 1/100 subjects, infrequent are those occurring 196 in 1/100 to 1/1,000 subjects, and rare are those occurring in fewer than 1/1,000 subjects. 197 Cardiovascular: Infrequent were hypertension, hypotension, bradycardia, tachycardia, 198 palpitations, and syncope. Rare was arrhythmia. 199 Gastrointestinal: Frequent was abdominal discomfort. 7 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 200 Musculoskeletal: Frequent were muscle cramps. 201 Neurological: Frequent was anxiety. Infrequent were mental confusion, euphoria, 202 agitation, tremor. Rare were myoclonia, sleep disturbance, and dystonia. 203 Respiratory: Infrequent was dyspnea. 204 Skin: Infrequent were erythema, pruritus, and skin rashes. 205 Miscellaneous: Infrequent was “serotonin agonist effect”. 206 Adverse Events Observed With Other Formulations of IMITREX: The following 207 adverse events occurred in clinical trials with IMITREX® Tablets and IMITREX® Nasal Spray. 208 Because the reports include events observed in open and uncontrolled trials, the role of 209 IMITREX in their causation cannot be reliably determined. All reported events are included 210 except those already listed, those too general to be informative, and those not reasonably 211 associated with the use of the drug. 212 Cardiovascular: Angina, cerebrovascular lesion, heart block, peripheral cyanosis, 213 phlebitis, thrombosis. 214 Gastrointestinal: Abdominal distention and colitis. 215 Neurological: Convulsions, hallucinations, syncope, suicide, and twitching. 216 Miscellaneous: Edema, hypersensitivity, swelling of extremities, and swelling of 217 face. 218 6.2 Postmarketing Experience 219 The following adverse reactions have been identified during postapproval use of 220 IMITREX Tablets, IMITREX Nasal Spray, and IMITREX Injection. Because these reactions are 221 reported voluntarily from a population of uncertain size, it is not always possible to reliably 222 estimate their frequency or establish a causal relationship to drug exposure. These reactions have 223 been chosen for inclusion due to either their seriousness, frequency of reporting, or causal 224 connection to IMITREX or a combination of these factors. 225 Blood: Hemolytic anemia, pancytopenia, thrombocytopenia. 226 Ear, Nose, and Throat: Deafness. 227 Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis. 228 Neurological: Central nervous system vasculitis, cerebrovascular accident, serotonin 229 syndrome, subarachnoid hemorrhage. 230 Non-Site Specific: Angioedema, cyanosis, temporal arteritis. 231 Skin: Exacerbation of sunburn, hypersensitivity reactions (allergic vasculitis, erythema, 232 pruritus, rash, shortness of breath, urticaria), photosensitivity. Following subcutaneous 233 administration of IMITREX, pain, redness, stinging, induration, swelling, contusion, 234 subcutaneous bleeding, and, on rare occasions, lipoatrophy (depression in the skin) or 235 lipohypertrophy (enlargement or thickening of tissue) have been reported. 236 Urogenital: Acute renal failure. 237 7 DRUG INTERACTIONS 238 7.1 Ergot-Containing Drugs Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 239 Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. 240 Because these effects may be additive, use of ergotamine-containing or ergot-type medications 241 (like dihydroergotamine or methysergide) and IMITREX Injection within 24 hours of each other 242 is contraindicated. 243 7.2 Monoamine Oxidase-A Inhibitors 244 MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of IMITREX 245 Injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology 246 (12.3)]. 247 7.3 Other 5-HT1 Agonists 248 Because their vasospastic effects may be additive, coadministration of IMITREX 249 Injection and other 5-HT1 agonists (e.g., triptans) within 24 hours of each other is 250 contraindicated. 251 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine 252 Reuptake Inhibitors and Serotonin Syndrome 253 Cases of serotonin syndrome have been reported during coadministration of triptans and 254 SSRIs, or SNRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)]. 255 8 USE IN SPECIFIC POPULATIONS 256 8.1 Pregnancy 257 Pregnancy Category C: There are no adequate and well-controlled trials of IMITREX 258 Injection in pregnant women. IMITREX Injection should be used during pregnancy only if the 259 potential benefit justifies the potential risk to the fetus. 260 When sumatriptan was administered intravenously to pregnant rabbits daily throughout 261 the period of organogenesis, embryolethality was observed at doses at or close to those 262 producing maternal toxicity. These doses were less than the maximum recommended human 263 dose (MRHD) of 12 mg/day on a mg/m2 basis. Oral administration of sumatriptan to rabbits 264 during organogenesis was associated with increased incidences of fetal vascular and skeletal 265 abnormalities. The highest no-effect dose for these effects was 15 mg/kg/day. The intravenous 266 administration of sumatriptan to pregnant rats throughout organogenesis at doses that are 267 approximately 10 times the MRHD on a mg/m2 basis, did not produce evidence of 268 embryolethality. The subcutaneous administration of sumatriptan to pregnant rats prior to and 269 throughout pregnancy did not produce evidence of embryolethality or teratogenicity. 270 8.3 Nursing Mothers 271 It is not known whether sumatriptan is excreted in human breast milk following 272 subcutaneous administration. Because many drugs are excreted in human milk, and because of 273 the potential for serious adverse reactions in nursing infants from IMITREX, a decision should 274 be made whether to discontinue nursing or to discontinue the drug, taking into account the 275 importance of the drug to the mother. 276 8.4 Pediatric Use Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 277 Safety and effectiveness of IMITREX Injection in pediatric patients under 18 years of 278 age have not been established; therefore, IMITREX Injection is not recommended for use in 279 patients under 18 years of age. 280 Two controlled clinical trials evaluated IMITREX Nasal Spray (5 to 20 mg) in 1,248 281 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not 282 establish the efficacy of IMITREX Nasal Spray compared with placebo in the treatment of 283 migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature 284 to those reported in clinical trials in adults. 285 Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating 286 oral IMITREX (25 to 100 mg) in pediatric subjects aged 12 to 17 years enrolled a total of 701 287 adolescent migraineurs. These trials did not establish the efficacy of oral IMITREX compared 288 with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these 289 clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of 290 all adverse reactions in these subjects appeared to be both dose- and age-dependent, with 291 younger subjects reporting reactions more commonly than older adolescents. 292 Postmarketing experience documents that serious adverse reactions have occurred in the 293 pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. These reports 294 include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, 295 and death. A myocardial infarction has been reported in a 14-year-old male following the use of 296 oral IMITREX; clinical signs occurred within 1 day of drug administration. Since clinical data to 297 determine the frequency of serious adverse reactions in pediatric patients who might receive 298 subcutaneous, oral, or intranasal IMITREX are not presently available, the use of IMITREX in 299 patients under 18 years of age is not recommended. 300 8.5 Geriatric Use 301 Clinical trials of IMITREX Injection did not include sufficient numbers of subjects aged 302 65 and over to determine whether they respond differently from younger subjects. Other reported 303 clinical experience has not identified differences in responses between the elderly and younger 304 subjects. In general, dose selection for an elderly patient should be cautious, usually starting at 305 the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or 306 cardiac function and of concomitant disease or other drug therapy. 307 A cardiovascular evaluation is recommended for geriatric patients who have other 308 cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history 309 of CAD) prior to receiving IMITREX Injection [see Warnings and Precautions (5.1)]. 310 10 OVERDOSAGE 311 No gross overdoses in clinical practice have been reported. Coronary vasospasm was 312 observed after intravenous administration of IMITREX Injection [see Contraindications (4)]. 313 Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly 314 cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 315 cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), 316 and paralysis. 317 The elimination half-life of sumatriptan is about 2 hours [see Clinical Pharmacology 318 (12.3)], and therefore monitoring of patients after overdose with IMITREX Injection should 319 continue for at least 10 hours or while symptoms or signs persist. 320 It is unknown what effect hemodialysis or peritoneal dialysis has on the serum 321 concentrations of sumatriptan. 322 11 DESCRIPTION 323 IMITREX Injection contains sumatriptan succinate, a selective 5-HT1B/1D receptor 324 agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N 325 methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: 326 structural formula 327 328 329 The empirical formula is C14H21N3O2SC4H6O4, representing a molecular weight of 330 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in 331 saline. 332 IMITREX Injection is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for 333 subcutaneous injection. Each 0.5 mL of IMITREX Injection 8 mg/mL solution contains 4 mg of 334 sumatriptan (base) as the succinate salt and 3.8 mg of sodium chloride, USP in Water for 335 Injection, USP. Each 0.5 mL of IMITREX Injection 12 mg/mL solution contains 6 mg of 336 sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for 337 Injection, USP. The pH range of both solutions is approximately 4.2 to 5.3. The osmolality of 338 both injections is 291 mOsmol. 339 12 CLINICAL PHARMACOLOGY 340 12.1 Mechanism of Action 341 Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. IMITREX 342 presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 343 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal 344 system. 345 Current theories proposed to explain the etiology of migraine headache suggest that 346 symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides 347 (including substance P and calcitonin gene-related peptide) through nerve endings in the 348 trigeminal system. The therapeutic activity of IMITREX for the treatment of migraine and 349 cluster headaches is thought to be due to the agonist effects at the 5-HT1B/1D receptors on 11 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 350 intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves o f the 351 trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory 352 neuropeptide release. 353 12.2 Pharmacody namics 354 Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, 355 has been reported in patients with and without a history of hypertension [see Warnings and 356 Precautions (5.8)]. 357 Peripheral (Small) Arteries: In healthy volunteers (N = 18), a trial evaluating the effects 358 o f suma triptan on peripheral (small vessel) arterial reactivity failed to detect a clinically 359 significant increase in peripheral resistance. 360 Heart Rate: Transient increases in blood pressure observed in some subjects in clinical 361 trials carried out during sumatriptan’s development as a treatment for migraine were not 362 accompanied by any clinically significant changes in heart rate. 363 12.3 Pharmacokinetics 364 Absorption and Bioavailability: The bioavailability of sumatriptan via subcutaneous site 365 injection to 18 healthy male subjects was 97%  16% of that obtained following intravenous 366 injection. 367 Aft er a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 368 healthy males (age: 24  6 years, weight: 70 kg), the maximum serum concentration (Cmax) of 369 sumatriptan was (mean  standard deviation) 74  15 ng/mL and the time to peak concentration 370 (Tmax) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected 371 subcutaneously in the thigh gave a Cmax of 61  15 ng/mL by manual injection versus 52  372 15 ng/mL by autoinjector techniques. The Tmax or amount absorbed was not significantly alt ered 373 by either the site or technique of injection. 374 Distribution: Protein binding, determined by equilibrium dialysis over the concentration 375 range of 10 to 1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the 376 protein binding of other drugs has not been evaluated. 377 Following a 6-mg subcutaneous injection into th e deltoid area of the arm in 9 males 378 ( mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of 379 sumatriptan was 50  8 liters and the distribution half-life was 15  2 minutes. 380 Metabolism: In vitro studies with human microsomes suggest that sumatriptan is 381 m etabo lized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of 382 sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA 383 glucuronide, both of which are inactive. 384 Elimination: After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine 385 as unchanged sumatriptan and 38%  7% as the IAA metabolite. 386 Following a 6-mg subcutaneous injection into the deltoid a rea of the arm, the systemic 387 clearance of sumatriptan was 1,194  149 mL/min and the terminal half-life was 115  388 19 minutes. Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 389 Special Populations: Age: The pharmacokinetics of sumatriptan in the elderly (mean 390 age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 391 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). 392 Renal Impairment: The effect of renal impairment on the pharmacokinetics of 393 sumatriptan has not been examined. 394 Hepatic Impairment: The effect of mild to moderate hepatic disease on the 395 pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were 396 no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in 397 moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics 398 of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not 399 been studied. The use of IMITREX Injection in this population is contraindicated [see 400 Contraindications (4)]. 401 Race: The systemic clearance and Cmax of sumatriptan were similar in black (n = 34) 402 and Caucasian (n = 38) healthy male subjects. 403 Drug Interaction Studies: Monoamine Oxidase-A Inhibitors: In a trial of 14 healthy 404 females, pretreatment with an MAO-A inhibitor decreased the clearance of sumatriptan, resulting 405 in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), 406 corresponding to a 40% increase in elimination half-life. 407 13 NONCLINICAL TOXICOLOGY 408 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 409 Carcinogenesis: In carcinogenicity studies, rats and mice were given sumatriptan by 410 oral gavage. Mice were dosed for 78 weeks and rats were dosed for 104 weeks. Average 411 exposures achieved in mice receiving the highest dose were approximately 110 times the 412 exposure attained in humans after the maximum recommended single dose of 6 mg. The highest 413 dose to rats was approximately 260 times the maximum single dose of 6 mg on a mg/m2 basis. 414 There was no evidence of an increase in tumors in either species related to sumatriptan 415 administration. 416 Mutagenesis: Sumatriptan was not mutagenic in the presence or absence of metabolic 417 activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian 418 Chinese hamster V79/HGPRT assay). It was not clastogenic in 2 cytogenetics assays (the in vitro 419 human lymphocyte assay and the in vivo rat micronucleus assay). 420 Impairment of Fertility: A fertility study (Segment I) by the subcutaneous route, during 421 which male and female rats were dosed daily with sumatriptan prior to and throughout the 422 mating period, has shown no evidence of impaired fertility at doses equivalent to approximately 423 100 times the maximum recommended single human dose of 6 mg on a mg/m2 basis. However, 424 following oral administration, a treatment-related decrease in fertility, secondary to a decrease in 425 mating, was seen for rats treated with 50 and 500 mg/kg/day. The no-effect dose for this finding 426 was approximately 8 times the maximum recommended single human dose of 6 mg on a mg/m2 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 427 basis. It is not clear whether the problem is associated with the treatment of males or females or 428 both. 429 13.2 Animal Toxicology and/or Pharmacology 430 Corneal Opacities: Dogs receiving oral sumatriptan developed corneal opacities and 431 defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 432 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium 433 were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and 434 no-effect doses were not established; however, the relative exposure at the lowest dose tested 435 was approximately 5 times the human exposure after a 100-mg oral dose or 3 times the human 436 exposure after a 6-mg subcutaneous dose. 437 Melanin Binding: In rats with a single subcutaneous dose (0.5 mg/kg) of radiolabeled 438 sumatriptan, the elimination half-life of radioactivity from the eye was 15 days, suggesting that 439 sumatriptan and its metabolites bind to the melanin of the eye. The clinical significance of this 440 binding is unknown. 441 14 CLINICAL STUDIES 442 14.1 Migraine 443 In controlled clinical trials enrolling more than 1,000 subjects during migraine attacks 444 who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in 445 Table 3, onset of relief began as early as 10 minutes following a 6-mg IMITREX Injection. 446 Lower doses of IMITREX Injection may also prove effective, although the proportion of subjects 447 obtaining adequate relief was decreased and the latency to that relief is greater with lower doses. 448 In Study 1, 6 different doses of IMITREX Injection (n = 30 each group) were compared 449 with placebo (n = 62), in a single-attack, parallel-group design, the dose response relationship 450 was found to be as shown in Table 2. 451 452 Table 2. Proportion of Subjects With Migraine Relief and Incidence of Adverse Events by 453 Time and by IMITREX Dose in Study 1 Dose of IMITREX Injection Percent Subjects With Reliefa Adverse Events Incidence (%) at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours Placebo 1 mg 2 mg 3 mg 4 mg 6 mg 8 mg 5 10 7 17 13 10 23 15 40 23 47 37 63 57 24 43 57 57 50 73 80 21 40 43 60 57 70 83 55 63 63 77 80 83 93 454 a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing 455 without use of rescue medication. Reference ID: 3198130 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 456 457 In 2 randomized, placebo-controlled clinical trials of IMITREX Injection 6 mg in 1,104 458 subjects with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 459 10 minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe 460 to mild or no headache, was achieved in 70% of the subjects within 1 hour of a single 6-mg 461 subcutaneous dose of IMITREX Injection. Approximately 82% and 65% of subjects treated with 462 IMITREX 6 mg had headache relief and were pain free within 2 hours, respectively. 463 Table 3 shows the 1- and 2-hour efficacy results for IMITREX Injection 6 mg in Studies 464 2 and 3. 465 466 Table 3. Proportion of Subjects With Pain Relief and Relief of Migraine Symptoms After 1 467 and 2 Hours of Treatment in Studies 2 and 3 1-Hour Data Study 2 Study 3 Placebo (n = 190) IMITREX 6 mg (n = 384) Placebo (n = 180) IMITREX 6 mg (n = 350) Subjects with pain relief (grade 0/1) 18% 70%a 26% 70%a Subjects with no pain 5% 48%a 13% 49%a Subjects without nausea 48% 73%a 50% 73%a Subjects without photophobia Subjects with little or no clinical 23% 56%a 25% 58%a disabilityb 34% 76%a 34% 76%a 2-Hour Data Study 2 Study 3 Placeboc IMITREX 6 mgd Placeboc IMITREX 6 mgd Subjects with pain relief (grade 0/1) 31% 81%a 39% 82%a Subjects with no pain 11% 63%a 19% 65%a Subjects without nausea 56% 82%a 63% 81%a Subjects without photophobia 31% 72%a 35% 71%a Subjects with little or no clinical disabilityb 42% 85%a 49% 84%a 468 a P<0.05 versus placebo. 469 b A successful outcome in terms of clinical disability was defined prospectively as ability to 470 work mildly impaired or ability to work and function normally. 471 c Includes subjects that may have received an additional placebo injection 1 hour after the initial 472 injection. 473 d Includes subjects that may have received an additional 6 mg of IMITREX Injection 1 hour 474 after the initial injection. 475 15 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 476 IMITREX Injection also relieved photophobia, phonophobia (sound sensitivity), nausea, 477 and vomiting associated with migraine attacks. Similar efficacy was seen when subjects 478 self-administered IMITREX Injection using the IMITREX STATdose Pen. 479 The efficacy of IMITREX Injection was unaffected by whether or not the migraine was 480 associated with aura, duration of attack, gender or age of the subject, or concomitant use of 481 common migraine prophylactic drugs (e.g., beta-blockers). 482 14.2 Cluster Headache 483 The efficacy of IMITREX Injection in the acute treatment of cluster headache was 484 demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period crossover trials 485 (Studies 4 and 5). Subjects aged 21 to 65 years were enrolled and were instructed to treat a 486 moderate to very severe headache within 10 minutes of onset. Headache relief was defined as a 487 reduction in headache severity to mild or no pain. In both trials, the proportion of individuals 488 gaining relief at 10 or 15 minutes was significantly greater among subjects receiving 6 mg of 489 IMITREX Injection compared with those who received placebo (see Table 4). 490 491 Table 4. Proportion of Subjects With Cluster Headache Relief by Time in Studies 4 and 5 Study 4 Study 5 Placebo (n = 39) IMITREX 6 mg (n = 39) Placebo (n = 88) IMITREX 6 mg (n = 92) Subjects with pain relief (no/mild) 5 Minutes post-injection 10 Minutes post-injection 15 Minutes post-injection 8% 10% 26% 21% 49%a 74%a 7% 25% 35% 23%a 49%a 75%a 492 a P<0.05. 493 (n = Number of headaches treated.) 494 495 An estimate of the cumulative probability of a subject with a cluster headache obtaining 496 relief after being treated with either IMITREX Injection or placebo is presented in Figure 1. 497 16 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 498 Figure 1. Time to Relief of Cluster Headache from Time of Injectiona 499 graph 501 a The figure uses Kaplan-Meier (product limit) Survivorship Plot. Subjects taking rescue 502 medication were censored at 15 minutes. 503 504 The plot was constructed with data from subjects who either experienced relief or did not 505 require (request) rescue medication within a period of 2 hours following treatment. As a 506 consequence, the data in the plot are derived from only a subset of the 258 headaches treated 507 (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 508 headaches treated with IMITREX Injection). 509 Other data suggest that treatment with IMITREX Injection is not associated with an 510 increase in early recurrence of headache and has little effect on the incidence of later-occurring 511 headaches (i.e., those occurring after 2, but before 18 or 24 hours). 512 16 HOW SUPPLIED/STORAGE AND HANDLING 513 IMITREX Injection contains sumatriptan (base) as the succinate salt and is supplied as a 514 clear, colorless to pale yellow, sterile, nonpyrogenic solution as follows: 515 Prefilled Syringe and/or Autoinjector Pen: Each pack contains a Patient Information and Patients 516 Instructions for Use leaflet. 517  IMITREX STATdose System®, 4 mg, containing 1 IMITREX STATdose Pen, 2 prefilled 518 single-dose syringe cartridges, and 1 carrying case (NDC 0173-0739-00). 519  IMITREX STATdose System, 6 mg, containing 1 IMITREX STATdose Pen, 2 prefilled 520 single-dose syringe cartridges, and 1 carrying case (NDC 0173-0479-00). 521  Two 4-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose System 522 (NDC 0173-0739-02). 523  Two 6-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose System 524 (NDC 0173-0478-00). 17 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 525 Single-Dose Vial: 526  IMITREX Injection single-dose vial (6 mg/0.5 mL) in cartons containing 5 vials (NDC 0173 527 0449-02). 528 Store between 2° and 30°C (36° and 86°F). Protect from light. 529 17 PATIENT COUNSELING INFORMATION 530 See FDA-approved patient labeling (Patient Information and Instructions for Use). 531 17.1 Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other 532 Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events 533 Inform patients that IMITREX Injection may cause serious cardiovascular side effects 534 such as myocardial infarction or stroke. Although serious cardiovascular events can occur 535 without warning symptoms, patients should be alert for the signs and symptoms of chest pain, 536 shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring 537 of speech and should ask for medical advice when observing any indicative sign or symptoms. 538 Patients should be apprised of the importance of this follow-up [see Warnings and Precautions 539 (5.1, 5.2, 5.4, 5.5, 5.8)]. 540 17.2 Anaphylactic/Anaphylactoid Reactions 541 Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients 542 receiving IMITREX Injection. Such reactions can be life threatening or fatal. In general, 543 anaphylactic reactions to drugs are more likely to occur in individuals with a history of 544 sensitivity to multiple allergens [see Warnings and Precautions (5.9)]. 545 17.3 Medication Overuse Headache 546 Inform patients that use of acute migraine drugs for 10 or more days per month may lead 547 to an exacerbation of headache and encourage patients to record headache frequency and drug 548 use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)]. 549 17.4 Pregnancy 550 Inform patients that IMITREX Injection should not be used during pregnancy unless the 551 potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. 552 17.5 Nursing Mothers 553 Advise patients to notify their healthcare provider if they are breastfeeding or plan to 554 breastfeed [see Use in Specific Populations (8.3)]. 555 17.6 Ability To Perform Complex Tasks 556 Since migraines or treatment with IMITREX Injection may cause somnolence and 557 dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine 558 attacks and after administration of IMITREX Injection. 559 17.7 Serotonin Syndrome 560 Patients should be cautioned about the risk of serotonin syndrome with the use of 561 IMITREX Injection or other triptans, particularly during combined use with SSRIs, SNRIs, 562 TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) and Drug Interactions (7.4)]. 563 17.8 How to Use IMITREX Injection Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c ompany logo 564 Provide patients instruction on the proper use of IMITREX Injection if they are able to 565 self-administer IMITREX Injection in medically unsupervised situation. 566 Inform patients that the needle in the IMITREX STATdose Pen penetrates approximately 567 1/4 of an inch (5 to 6 mm). Inform patients that the injection is intended to be given 568 subcutaneously and intramuscular or intravascular delivery should be avoided. Instruct patients 569 to use injection sites with an adequate skin and subcutaneous thickness to accommodate the 570 length of the needle. 571 572 IMITREX, IMITREX STATdose Pen, and IMITREX STATdose System are registered 573 trademarks of GlaxoSmithKline. 574 575 576 577 GlaxoSmithKline 578 Research Triangle Park, NC 27709 579 580 ©2012, GlaxoSmithKline. All rights reserved. 581 582 583 Patient Information 584 IMITREX® (IM-i-trex) 585 (sumatriptan succinate) 586 Injection 587 588 Read this Patient Information before you start taking IMITREX and each time you get a refill. 589 There may be new information. This information does not take the place of talking with your 590 healthcare provider about your medical condition or treatment. 591 592 What is the most important information I should know about IMITREX? 593 IMITREX can cause serious side effects, including: 594 Heart attack and other heart problems. Heart problems may lead to death. 595 Stop taking IMITREX and get emergency medical help right away if you have any of the 596 following symptoms of a heart attack: 597  discomfort in the center of your chest that lasts for more than a few minutes, or that goes 598 away and comes back 599  severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw 600  pain or discomfort in your arms, back, neck, jaw, or stomach 601  shortness of breath with or without chest discomfort 19 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 602  breaking out in a cold sweat 603  nausea or vomiting 604  feeling lightheaded 605 IMITREX is not for people with risk factors for heart disease unless a heart exam is done and 606 shows no problem. You have a higher risk for heart disease if you: 607  have high blood pressure 608  have high cholesterol levels 609  smoke 610  are overweight 611  have diabetes 612  have a family history of heart disease 613 614 What is IMITREX? 615 IMITREX is a prescription medicine used to treat acute migraine headaches with or without aura 616 and acute cluster headaches in adults who have been diagnosed with migraine or cluster 617 headaches. 618 IMITREX is not used to treat other types of headaches such as hemiplegic (that make you unable 619 to move on one side of your body) or basilar (rare form of migraine with aura) migraines. IMITREX is not used to prevent or decrease the number of migraine or cluster headaches you have. 620 It is not known if IMITREX is safe and effective in children under 18 years of age. 621 622 Who should not take IMITREX? 623 Do not take IMITREX if you have: 624  heart problems or a history of heart problems 625  narrowing of blood vessels to your legs, arms, stomach, or kidney (peripheral vascular 626 disease) 627  uncontrolled high blood pressure 628  hemiplegic migraines or basilar migraines. If you are not sure if you have these types of 629 migraines, ask your healthcare provider. 630  had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation 631  taken any of the following medicines in the last 24 hours: 632  almotriptan (AXERT®) 633  eletriptan (RELPAX®) 634  frovatriptan (FROVA®) 635  naratriptan (AMERGE®) 636  rizatriptan (MAXALT®, MAXALT-MLT®) 637  sumatriptan and naproxen (TREXIMET®) 20 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 638  ergotamines (CAFERGOT®, ERGOMAR®, MIGERGOT®) 639  dihydroergotamine (D.H.E. 45®, MIGRANAL®) 640 Ask your healthcare provider if you are not sure if your medicine is listed above. 641  an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of this leaflet for 642 a complete list of ingredients in IMITREX. 643 644 What should I tell my healthcare provider before taking IMITREX? 645 Before you take IMITREX, tell your healthcare provider about all of your medical conditions, 646 including if you: 647  have high blood pressure 648  have high cholesterol 649  have diabetes 650  smoke 651  are overweight 652  have heart problems or family history of heart problems or stroke 653  have liver problems 654  have had epilepsy or seizures 655  are not using effective birth control 656  become pregnant while taking IMITREX 657  are breastfeeding or plan to breastfeed. IMITREX passes into your breast milk and may harm 658 your baby. Talk with your healthcare provider about the best way to feed your baby if you 659 take IMITREX. 660 Tell your healthcare provider about all the medicines you take, including prescription and 661 nonprescription medicines, vitamins, and herbal supplements. 662 Using IMITREX with certain other medicines can affect each other, causing serious side effects. 663 Especially tell your healthcare provider if you take anti-depressant medicines called: 664  selective serotonin reuptake inhibitors (SSRIs) 665  serotonin norepinephrine reuptake inhibitors (SNRIs) 666  tricyclic antidepressants (TCAs) 667  monoamine oxidase inhibitors (MAOIs) 668 Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. 669 Know the medicines you take. Keep a list of them to show your healthcare provider or 670 pharmacist when you get a new medicine. 671 672 How should I take IMITREX? 21 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 673  Certain people should take their first dose of IMITREX in their healthcare provider’s office 674 or in another medical setting. Ask your healthcare provider if you should take your first dose 675 in a medical setting. 676  Use IMITREX exactly as your healthcare provider tells you to use it. 677  Your healthcare provider may change your dose. Do not change your dose without first 678 talking with your healthcare provider. 679  For adults, the usual dose is a single injection given just below the skin. 680  You should give an injection as soon as the symptoms of your headache start, but it may be 681 given at any time during a migraine attack. 682  If you did not get any relief after the first injection, do not give a second injection without 683 first talking with your healthcare provider. 684  You can take a second injection 1 hour after the first injection, but not sooner, if your 685 headache came back after your first injection. 686  Do not take more than 12 mg in a 24-hour period. 687  If you use too much IMITREX, call your healthcare provider or go to the nearest hospital 688 emergency room right away. 689  You should write down when you have headaches and when you take IMITREX so you can 690 talk with your healthcare provider about how IMITREX is working for you. 691 692 What should I avoid while taking IMITREX? 693 IMITREX can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not 694 drive a car, use machinery, or do anything where you need to be alert. 695 696 What are the possible side effects of IMITREX? 697 IMITREX may cause serious side effects. See “What is the most important information I 698 should know about IMITREX?” 699 These serious side effects include: 700  changes in color or sensation in your fingers and toes (Raynaud’s syndrome) 701  stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of 702 gastrointestinal and colonic ischemic events include: 703  sudden or severe stomach pain 704  stomach pain after meals 705  weight loss 706  nausea or vomiting 707  constipation or diarrhea 708  bloody diarrhea 709  fever 710  problems with blood circulation to your legs and feet (peripheral vascular ischemia). 711 Symptoms of peripheral vascular ischemia include: 22 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 712  cramping and pain in your legs or hips 713  feeling of heaviness or tightness in your leg muscles 714  burning or aching pain in your feet or toes while resting 715  numbness, tingling, or weakness in your legs 716  cold feeling or color changes in 1 or both legs or feet 717  medication overuse headaches. Some people who use too many IMITREX injections may 718 have worse headaches (medication overuse headache). If your headaches get worse, your 719 healthcare provider may decide to stop your treatment with IMITREX. 720  serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in 721 people using IMITREX, especially if IMITREX is used with anti-depressant medicines 722 called SSRIs or SNRIs. 723 Call your healthcare provider right away if you have any of the following symptoms of 724 serotonin syndrome: 725  mental changes such as seeing things that are not there (hallucinations), agitation, or 726 coma 727  fast heartbeat 728  changes in blood pressure 729  high body temperature 730  tight muscles 731  trouble walking 732  seizures. Seizures have happened in people taking IMITREX who have never had seizures 733 before. Talk with your healthcare provider about your chance of having seizures while you 734 take IMITREX. 735 The most common side effects of IMITREX include: 736  pain or redness at your injection site 737  tingling or numbness in your fingers or toes 738  dizziness 739  warm, hot, burning feeling to your face (flushing) 740  discomfort or stiffness in your neck 741  feeling weak, drowsy, or tired 742 Tell your healthcare provider if you have any side effect that bothers you or that does not go 743 away. 744 These are not all the possible side effects of IMITREX. For more information, ask your 745 healthcare provider or pharmacist. 746 Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 747 800-FDA-1088. 748 23 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c o mpany logo 749 How should I store IMITREX Injection? 750  Store IMITREX between 36°F to 86°F (2°C to 30°C). 751  Store your medicine away from light. 752  Keep your medicine in the packaging or carrying case provided with it. 753 Keep IMITREX and all medicines out of the reach of children. 754 755 General information about the safe and effective use of IMITREX 756 Medicines are sometimes prescribed for purposes other than those listed in Patient Information 757 leaflets. Do not use IMITREX for a condition for which it was not prescribed. Do not give 758 IMITREX to other people, even if they have the same symptoms you have. It may harm them. 759 This Patient Information leaflet summarizes the most important information about IMITREX. If 760 you would like more information, talk with your healthcare provider. You can ask your 761 healthcare provider or pharmacist for information about IMITREX that is written for healthcare 762 professionals. 763 For more information, go to www.gsk.com or call 1-888-825-5249. 764 765 What are the ingredients in IMITREX Injection? 766 Active ingredient: sumatriptan succinate 767 Inactive ingredients: sodium chloride, water for injection 768 769 This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug 770 Administration. 771 772 IMITREX, AMERGE, TREXIMET are registered trademarks of GlaxoSmithKline. The other 773 brands listed are trademarks of their respective owners and are not trademarks of 774 GlaxoSmithKline. The makers of these brands are not affiliated with and do not endorse 775 GlaxoSmithKline or its products. 776 781 782 ©2012, GlaxoSmithKline. All rights reserved. 783 784 September 2012 785 24 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 10 35 15 20 25 30 1 Patient Information 2 IMITREX® (IM-i-trex) 3 (sumatriptan succinate) 4 Injection 6 Read this Patient Information before you start taking IMITREX and each time you 7 get a refill. There may be new information. This information does not take the place 8 of talking with your healthcare provider about your medical condition or treatment. 9 What is the most important information I should know about IMITREX? 11 IMITREX can cause serious side effects, including: 12 Heart attack and other heart problems. Heart problems may lead to death. 13 Stop taking IMITREX and get emergency medical help right away if you 14 have any of the following symptoms of a heart attack:  discomfort in the center of your chest that lasts for more than a few minutes, or 16 that goes away and comes back 17  severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw 18  pain or discomfort in your arms, back, neck, jaw, or stomach 19  shortness of breath with or without chest discomfort  breaking out in a cold sweat 21  nausea or vomiting 22  feeling lightheaded 23 IMITREX is not for people with risk factors for heart disease unless a heart exam is 24 done and shows no problem. You have a higher risk for heart disease if you:  have high blood pressure 26  have high cholesterol levels 27  smoke 28  are overweight 29  have diabetes  have a family history of heart disease 31 32 What is IMITREX? 33 IMITREX is a prescription medicine used to treat acute migraine headaches with or 34 without aura and acute cluster headaches in adults who have been diagnosed with migraine or cluster headaches. 36 IMITREX is not used to treat other types of headaches such as hemiplegic (that 37 make you unable to move on one side of your body) or basilar (rare form of 38 migraine with aura) migraines. 1 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMITREX is not used to prevent or decrease the number of migraine or cluster headaches you have. 39 It is not known if IMITREX is safe and effective in children under 18 years of age. 40 41 Who should not take IMITREX? 42 Do not take IMITREX if you have: 43  heart problems or a history of heart problems 44  narrowing of blood vessels to your legs, arms, stomach, or kidney (peripheral 45 vascular disease) 46  uncontrolled high blood pressure 47  hemiplegic migraines or basilar migraines. If you are not sure if you have these 48 types of migraines, ask your healthcare provider. 49  had a stroke, transient ischemic attacks (TIAs), or problems with your blood 50 circulation 51  taken any of the following medicines in the last 24 hours: 52  almotriptan (AXERT®) 53  eletriptan (RELPAX®) 54  frovatriptan (FROVA®) 55  naratriptan (AMERGE®) 56  rizatriptan (MAXALT®, MAXALT-MLT®) 57  sumatriptan and naproxen (TREXIMET®) 58  ergotamines (CAFERGOT®, ERGOMAR®, MIGERGOT®) 59  dihydroergotamine (D.H.E. 45®, MIGRANAL®) 60 Ask your healthcare provider if you are not sure if your medicine is listed above. 61  an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of 62 this leaflet for a complete list of ingredients in IMITREX. 63 64 What should I tell my healthcare provider before taking IMITREX? 65 Before you take IMITREX, tell your healthcare provider about all of your medical 66 conditions, including if you: 67  have high blood pressure 68  have high cholesterol 69  have diabetes 70  smoke 71  are overweight 72  have heart problems or family history of heart problems or stroke 73  have liver problems 74  have had epilepsy or seizures 75  are not using effective birth control 2 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 76  become pregnant while taking IMITREX 77  are breastfeeding or plan to breastfeed. IMITREX passes into your breast milk 78 and may harm your baby. Talk with your healthcare provider about the best way 79 to feed your baby if you take IMITREX. 80 Tell your healthcare provider about all the medicines you take, including 81 prescription and nonprescription medicines, vitamins, and herbal supplements. 82 Using IMITREX with certain other medicines can affect each other, causing serious 83 side effects. 84 Especially tell your healthcare provider if you take anti-depressant medicines 85 called: 86  selective serotonin reuptake inhibitors (SSRIs) 87  serotonin norepinephrine reuptake inhibitors (SNRIs) 88  tricyclic antidepressants (TCAs) 89  monoamine oxidase inhibitors (MAOIs) 90 Ask your healthcare provider or pharmacist for a list of these medicines if you are 91 not sure. 92 Know the medicines you take. Keep a list of them to show your healthcare provider 93 or pharmacist when you get a new medicine. 94 95 How should I take IMITREX? 96  Certain people should take their first dose of IMITREX in their healthcare 97 provider’s office or in another medical setting. Ask your healthcare provider if 98 you should take your first dose in a medical setting. 99  Use IMITREX exactly as your healthcare provider tells you to use it. 100  Your healthcare provider may change your dose. Do not change your dose 101 without first talking with your healthcare provider. 102  For adults, the usual dose is a single injection given just below the skin. 103  You should give an injection as soon as the symptoms of your headache start, 104 but it may be given at any time during a migraine attack. 105  If you did not get any relief after the first injection, do not give a second 106 injection without first talking with your healthcare provider. 107  You can take a second injection 1 hour after the first injection, but not sooner, if 108 your headache came back after your first injection. 109  Do not take more than 12 mg in a 24-hour period. 110  If you use too much IMITREX, call your healthcare provider or go to the nearest 111 hospital emergency room right away. 3 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 112  You should write down when you have headaches and when you take IMITREX 113 so you can talk with your healthcare provider about how IMITREX is working for 114 you. 115 116 What should I avoid while taking IMITREX? 117 IMITREX can cause dizziness, weakness, or drowsiness. If you have these 118 symptoms, do not drive a car, use machinery, or do anything where you need to be 119 alert. 120 121 What are the possible side effects of IMITREX? 122 IMITREX may cause serious side effects. See “What is the most important 123 information I should know about IMITREX?” 124 These serious side effects include: 125  changes in color or sensation in your fingers and toes (Raynaud’s syndrome) 126  stomach and intestinal problems (gastrointestinal and colonic ischemic events). 127 Symptoms of gastrointestinal and colonic ischemic events include: 128  sudden or severe stomach pain 129  stomach pain after meals 130  weight loss 131  nausea or vomiting 132  constipation or diarrhea 133  bloody diarrhea 134  fever 135  problems with blood circulation to your legs and feet (peripheral vascular 136 ischemia). Symptoms of peripheral vascular ischemia include: 137  cramping and pain in your legs or hips 138  feeling of heaviness or tightness in your leg muscles 139  burning or aching pain in your feet or toes while resting 140  numbness, tingling, or weakness in your legs 141  cold feeling or color changes in 1 or both legs or feet 142  medication overuse headaches. Some people who use too many IMITREX 143 injections may have worse headaches (medication overuse headache). If your 144 headaches get worse, your healthcare provider may decide to stop your treatment with IMITREX. 146  serotonin syndrome. Serotonin syndrome is a rare but serious problem that can 147 145 happen in people using IMITREX, especially if IMITREX is used with anti-depressant medicines called SSRIs or SNRIs. 148 Call your healthcare provider right away if you have any of the following 149 symptoms of serotonin syndrome: 150 4 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 151  mental changes such as seeing things that are not there (hallucinations), agitation, or coma 153  fast heartbeat 154  changes in blood pressure 155  high body temperature 156  tight muscles 157  trouble walking 158  seizures. Seizures have happened in people taking IMITREX who have never had 159 seizures before. Talk with your healthcare provider about your chance of having 160 seizures while you take IMITREX. 152 161 The most common side effects of IMITREX include: 162  pain or redness at your injection site 163  tingling or numbness in your fingers or toes 164  dizziness 165  warm, hot, burning feeling to your face (flushing) 166  discomfort or stiffness in your neck 167  feeling weak, drowsy, or tired 168 Tell your healthcare provider if you have any side effect that bothers you or that 169 does not go away. 170 These are not all the possible side effects of IMITREX. For more information, ask 171 your healthcare provider or pharmacist. 172 Call your doctor for medical advice about side effects. You may report side effects 173 to FDA at 1-800-FDA-1088. 174 175 How should I store IMITREX Injection? 176  Store IMITREX between 36°F to 86°F (2°C to 30°C). 177  Store your medicine away from light. 178  Keep your medicine in the packaging or carrying case provided with it. 179 Keep IMITREX and all medicines out of the reach of children. 180 181 General information about the safe and effective use of IMITREX 182 Medicines are sometimes prescribed for purposes other than those listed in Patient 183 Information leaflets. Do not use IMITREX for a condition for which it was not 184 prescribed. Do not give IMITREX to other people, even if they have the same 185 symptoms you have. It may harm them. 186 This Patient Information leaflet summarizes the most important information about 187 IMITREX. If you would like more information, talk with your healthcare provider. 5 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda u s a g e illustration 188 You can ask your healthcare provider or pharmacist for information about IMITREX 189 that is written for healthcare professionals. 190 For more information, go to www.gsk.com or call 1-888-825-5249. 191 192 What are the ingredients in IMITREX Injection? 193 Active ingredient: sumatriptan succinate 194 Inactive ingredients: sodium chloride, water for injection 195 196 Month Year 197 IMJ:xPPI 198 199 200 201 202 203 Read this Patient Instructions for Use before you start to use the IMITREX STATdose System. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about IMITREX Injection when you start taking it and at regular checkups. 204 Keep the IMITREX STATdose System out of the reach of children. 205 Before you use the IMITREX STATdose System 206 207 When you first open the IMITREX STATdose System box, the Cartridge Pack and the IMITREX STATdose Pen® are already in the Carrying Case for your convenience. 209 210 211 The grey and blue Carrying Case is used for storing the unloaded Pen and the Cartridge Pack when they are not being used. 212 213 214 215 216 The Cartridge Pack holds 2 individually sealed Syringe Cartridges. Each Syringe Cartridge holds 1 dose of IMITREX® (sumatriptan succinate) Injection. The Cartridge Pack for the 4-mg strength of this 208 6 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration 217 medicine is yellow, and the Cartridge Pack for the 6-mg strength is blue (as shown). Refill 218 Cartridge Packs are available. 219 220 The grey and blue Pen is used to automatically inject 1 dose of medicine from a 221 Syringe Cartridge. Do not touch the Blue Button until you have pressed the Pen 222 against your skin to give a dose. If you press it at any other time, you might lose a 223 dose. The Safety Catch keeps the Pen from accidentally firing until you are ready. 224 The Pen will only work when you slide the grey part of the barrel down to the blue 225 part. Always check to make sure that the white Priming Rod is not sticking out from 226 the end of the Pen (as shown in Figure B) before you load a new Syringe Cartridge. 227 If it is sticking out, you will lose that dose. 228 How to load the IMITREX STATdose Pen 229 Do not load the Pen until you are ready to give yourself an injection. 230 Do not touch the Blue Button on top of the Pen (see Figure A) 231 while you are loading the Pen. 232 240 1. Open the lid of the Carrying Case. The tamper 241 evident seals over the 2 Syringe Cartridges are 242 labeled “A” and “B” (see Figure A inset). 243 Always use the Syringe Cartridge marked “A” 244 before the one marked “B” to help you keep 245 track of your doses. Do not use if either 246 seal is broken or missing when you first 233 247 open the Carrying Case. 234 235 248 2. Tear off one of the tamper-evident seals (see 249 Figure A). Throw away the seal. Open the lid 236 250 over the Syringe Cartridge. 251 3. Hold the Pen by the ridges at the top. Take 252 the Pen out of the Carrying Case (see Figure 253 B). 254 Check to make sure the white Priming Rod is 255 not sticking out from the lower end of the Pen 256 (see Figure B inset). If it is sticking out, put 257 the Pen back into the Carrying Case and press 237 238 258 down firmly until you feel it click. Take the 239 259 Pen out of the Carrying Case. usage illustration Figure A Figure B 7 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 264 4. Put the Pen in the Cartridge Pack. Turn it to 265 the right (clockwise) until it will not turn any 266 more (about half a turn) (see Figure C). 267 268 269 270 271 261 Figure C 272 5. Hold the loaded Pen by the ridges and pull it 273 straight out (see Figure D). You may need 274 to pull hard on the Pen, but this is normal. Do 275 not press the Blue Button yet. 262 263 276 The Pen is now ready to use. Do not put the loaded Pen back into the Carrying 277 Case because that will damage the needle. usage illustrationusage illustration Figure D 278 How to use the IMITREX STATdose Pen to take your medicine 279 Before injecting your medicine, choose an area with a fatty tissue layer (see Figure 280 E or Figure F). Ask your healthcare provider if you have a question about where to 281 inject your medicine. 282 To prepare the area of skin where IMITREX is to be injected, wipe the injection site 283 with an alcohol swab. Do not touch this area again before giving the injection. 284 usag e il lustration 288 Figure E or Figure F Figure G 289 6. Without pushing the Blue Button, press the loaded Pen firmly against the skin 290 so that the grey barrel slides down toward the blue section that holds the 8 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration 291 Syringe Cartridge (see Figure D). (This releases the Safety Catch that keeps the Pen from firing by mistake until you are ready.) 293 7. Push the Blue Button. Hold the Pen still for at least 5 seconds. If the Pen is 294 292 taken away from the skin too soon, not all the medicine will come out. 295 8. After 5 seconds, carefully take the Pen away from your skin. The needle will 296 be showing (see Figure G). Do not touch the needle. 297 How to unload the IMITREX STATdose Pen after taking your medicine 298 Right after you take a dose with the Pen, you need to return the used Syringe 299 Cartridge to the Cartridge Pack. usage illustrationusage illustration Figure J 300 302 301 Figure H 303 Figure I 304 305 306 9. Push the Pen down into the empty side of the Cartridge Pack as far as it will go 307 (see Figure H). 308 10. Turn the Pen to the left (counterclockwise) about half a turn until it is released 309 from the Syringe Cartridge (see Figure I). 310 11. Pull the empty Pen out of the Cartridge Pack (see Figure J). 311 Because the Pen has now been used, the white Priming Rod will stick out from 312 the lower end of the Pen (see Figure J). 313 12. Close the Cartridge Pack lid over the used Syringe Cartridge. When the used 314 Syringe Cartridges are inserted correctly, the Cartridge Pack is a disposable, 315 protective case to help you avoid needle sticks and use the syringes correctly. 316 13. Put the Pen back into the Carrying Case and press it down firmly until you feel 317 it click. Close the Carrying Case lid. This gets the Pen ready for the next use. If the lid will not close, push the Pen down until you feel it click. Then close the 319 lid. 318 9 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration 320 How to take out a used Cartridge Pack 321 After both Syringe Cartridges have been used, take the Cartridge Pack out of the 322 Carrying Case. Never reuse or recycle a Syringe Cartridge. usage illustrationusage illustration Figure L 323 325 324 Figure K 326 327 14. Open the Carrying Case lid. 328 15. Hold the Carrying Case with one hand and press the 2 buttons on either side of 329 the Carrying Case (see Figure K). 330 16. Gently pull out the Cartridge Pack with the other hand (see Figure L). 331 17. Throw away the Cartridge Pack or dispose of it as instructed by your healthcare 332 provider. There may be special state and local laws for disposing of used 333 needles and syringes. Always keep out of the reach of children. 334 How to insert a new Cartridge Pack 335 usage illustrationusage illustration Figure O 336 340 338 337 339 Figure N 341 342 17. Take the new Cartridge Pack out of its box. Do not take off the 343 tamper-evident seals (see Figure M). 344 18. Put the Cartridge Pack in the Carrying Case. Slide it down smoothly (see 345 Figure N). 346 19. The Cartridge Pack will click into place when the 2 buttons show through the 347 holes in the Carrying Case (see Figure O). Close the lid. 348 Figure M 10 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 349 This Patient Information and Instructions for Use has been approved by the U.S. 350 Food and Drug Administration. 351 352 AMERGE, IMITREX, IMITREX STATdose System, IMITREX STATdose Pen, and 353 TREXIMET are registered trademarks of GlaxoSmithKline. The other brands listed 354 are trademarks of their respective owners and are not trademarks of 355 GlaxoSmithKline. The makers of these brands are not affiliated with and do not 356 endorse GlaxoSmithKline or its products. 357 comp any logo 360 GlaxoSmithKline 361 Research Triangle Park, NC 27709 362 363 ©2012, GlaxoSmithKline. All rights reserved. 364 365 Month Year 366 IMJ:xPIL 11 Reference ID: 3198130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:41.401460	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020080s039s040s041s045lbl.pdf', 'application_number': 20080, 'submission_type': 'SUPPL ', 'submission_number': 40}
12,189	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IMITREX safely and effectively. See full prescribing information for IMITREX. IMITREX (sumatriptan succinate) injection, for subcutaneous use Initial U.S. Approval: 1992 --------------------------- INDICATIONS AND USAGE ---------------------------- IMITREX Injection is a serotonin (5-HT1B/1D) receptor agonist (triptan) indicated for:  Acute treatment of migraine with or without aura in adults (1)  Acute treatment of cluster headache in adults (1) Limitations of Use:  Use only if a clear diagnosis of migraine or cluster headache has been established (1)  Not indicated for the prophylactic therapy of migraine or cluster headache attacks (1) ----------------------- DOSAGE AND ADMINISTRATION -----------------------  For subcutaneous use only (2.1)  Acute treatment of migraine: single dose of 1 to 6 mg (2.1)  Acute treatment of cluster headache: single dose of 6 mg (2.1)  Maximum dose in a 24-hour period: 12 mg, separate doses by at least 1 hour (2.1)  Patients receiving doses other than 4 or 6 mg: Use the 6-mg single-dose vial (2.3) --------------------- DOSAGE FORMS AND STRENGTHS----------------------  Injection: 4- and 6-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose Pen (3)  Injection: 6-mg single-dose vial (3) ------------------------------ CONTRAINDICATIONS ------------------------------  History of coronary artery disease or coronary artery vasospasm (4)  Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders (4)  History of stroke, transient ischemic attack, or hemiplegic or basilar migraine (4)  Peripheral vascular disease (4)  Ischemic bowel disease (4)  Uncontrolled hypertension (4)  Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another triptan) or of an ergotamine-containing medication (4)  Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor (4)  Hypersensitivity to IMITREX (angioedema and anaphylaxis seen) (4)  Severe hepatic impairment (4) ----------------------- WARNINGS AND PRECAUTIONS -----------------------  Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors (5.1)  Arrhythmias: Discontinue IMITREX if occurs (5.2)  Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk (5.3)  Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue IMITREX if occurs (5.4)  Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue IMITREX if occurs (5.5)  Medication overuse headache: Detoxification may be necessary (5.6)  Serotonin syndrome: Discontinue IMITREX if occurs (5.7)  Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold (5.10) ------------------------------ ADVERSE REACTIONS ------------------------------ Most common adverse reactions (5% and >placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------- USE IN SPECIFIC POPULATIONS ----------------------- Pregnancy: Based on animal data, may cause fetal harm (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: x/xxxx FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Administration Using the IMITREX STATdose Pen® 2.3 Administration of Doses of IMITREX other than 4 or 6 mg 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina 5.2 Arrhythmias 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 5.4 Cerebrovascular Events 5.5 Other Vasospasm Reactions 5.6 Medication Overuse Headache 5.7 Serotonin Syndrome 5.8 Increase in Blood Pressure 5.9 Anaphylactic/Anaphylactoid Reactions 5.10 Seizures 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Ergot-containing Drugs 7.2 Monoamine Oxidase-A Inhibitors 7.3 Other 5-HT1 Agonists 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Migraine 14.2 Cluster Headache 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE IMITREX® Injection is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache. Limitations of Use:  Use only if a clear diagnosis of migraine or cluster headache has been established. If a patient has no response to the first migraine or cluster headache attack treated with IMITREX Injection, reconsider the diagnosis before IMITREX Injection is administered to treat any subsequent attacks.  IMITREX Injection is not indicated for the prevention of migraine or cluster headache attacks. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The maximum single recommended adult dose of IMITREX Injection for the acute treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of migraine, if side effects are dose limiting, lower doses (1 mg to 5 mg) may be used [see Clinical Studies (14.1)]. For the treatment of cluster headache, the efficacy of lower doses has not been established. The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg injections separated by at least 1 hour. A second 6-mg dose should only be considered if some response to a first injection was observed. 2.2 Administration Using the IMITREX STATdose Pen® An autoinjector device (IMITREX STATdose Pen) is available for use with 4- mg and 6-mg prefilled syringe cartridges. With this device, the needle penetrates approximately 1/4 inch (5 to 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular delivery must be avoided. Instruct patients on the proper use of IMITREX STATdose Pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. 2.3 Administration of Doses of IMITREX Other than 4 or 6 mg In patients receiving doses other than 4 mg or 6 mg, use the 6-mg single-dose vial; do not use the IMITREX STATdose Pen. Visually inspect the vial for particulate matter and discoloration before administration. Do not use if particulates and discolorations are noted. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 DOSAGE FORMS AND STRENGTHS  Injection: 4-mg and 6-mg single-dose prefilled syringe cartridges for use with the IMITREX STATdose Pen.  Injection: 6-mg single-dose vial. 4 CONTRAINDICATIONS IMITREX Injection is contraindicated in patients with:  Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina [see Warnings and Precautions (5.1)].  Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2)].  History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see Warnings and Precautions (5.4)].  Peripheral vascular disease [see Warnings and Precautions (5.5)].  Ischemic bowel disease [see Warnings and Precautions (5.5)].  Uncontrolled hypertension [see Warnings and Precautions (5.8)].  Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT1) agonist [see Drug Interactions (7.1, 7.3)].  Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].  Hypersensitivity to IMITREX (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.9)].  Severe hepatic impairment [see Clinical Pharmacology (12.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina The use of IMITREX Injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of IMITREX Injection. Some of these reactions occurred in patients without known CAD. IMITREX Injection may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX Injection. If there is evidence of CAD or coronary artery vasospasm, IMITREX Injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of IMITREX Injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of IMITREX Injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of IMITREX Injection. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue IMITREX Injection if these disturbances occur. IMITREX Injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with IMITREX Injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of IMITREX Injection is contraindicated in patients with CAD and those with Prinzmetal’s variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue IMITREX Injection if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed with migraine or cluster headache or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. IMITREX Injection is contraindicated in patients with a history of stroke or TIA. 5.5 Other Vasospasm Reactions IMITREX Injection may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional IMITREX Injections. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with IMITREX Injection, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.4)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue IMITREX Injection if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with IMITREX. IMITREX Injection is contraindicated in patients with uncontrolled hypertension. 5.9 Anaphylactic/Anaphylactoid Reactions Anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. IMITREX Injection is contraindicated in patients with a history of hypersensitivity reaction to IMITREX. 5.10 Seizures Seizures have been reported following administration of IMITREX. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. IMITREX Injection Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling:  Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina [see Warnings and Precautions (5.1)]  Arrhythmias [see Warnings and Precautions (5.2)]  Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)]  Cerebrovascular events [see Warnings and Precautions (5.4)]  Other vasospasm reactions [see Warnings and Precautions (5.5)]  Medication overuse headache [see Warnings and Precautions (5.6)]  Serotonin syndrome [see Warnings and Precautions (5.7)]  Increase in blood pressure [see Warnings and Precautions (5.8)]  Hypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.9)]  Seizures [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Migraine Headache Table 1 lists adverse reactions that occurred in 2 US placebo-controlled clinical trials in migraine patients (Studies 2 and 3) following either a single 6-mg dose of IMITREX Injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with IMITREX Injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3) IMITREX Injection 6 mg Subcutaneous (n = 547) % Placebo (n = 370) % Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort 5 1 Tightness in chest 3 <1 Pressure in chest 2 <1 Ear, nose, and throat Throat discomfort Discomfort: nasal cavity/sinuses 3 2 <1 <1 Injection site reactiona 59 24 Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness 5 <1 Neck pain/stiffness 5 <1 Myalgia 2 <1 Neurological Dizziness/vertigo 12 4 Drowsiness/sedation 3 2 Headache 2 <1 Skin Sweating 2 1 a Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Cluster Headache In the controlled clinical trials assessing the efficacy of IMITREX Injection as a treatment for cluster headache (Studies 4 and 5), no new significant adverse reactions were detected that had not already been identified in trials of IMITREX in patients with migraine. Overall, the frequency of adverse reactions reported in the trials of cluster headache was generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% IMITREX, 0% placebo), nausea and vomiting (4% IMITREX, 0% placebo), and bronchospasm (1% IMITREX, 0% placebo). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of IMITREX Tablets, IMITREX Nasal Spray, and IMITREX Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Hypotension, palpitations. Neurological Dystonia, tremor. 7 DRUG INTERACTIONS 7.1 Ergot-containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and IMITREX Injection within 24 hours of each other is contraindicated. 7.2 Monoamine Oxidase-A Inhibitors MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of IMITREX Injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology (12.3)]. 7.3 Other 5-HT1 Agonists Because their vasospastic effects may be additive, co-administration of IMITREX Injection and other 5-HT1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled trials of IMITREX Injection in pregnant women. In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal. IMITREX Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rates was 60 mg/kg/day, or approximately 100 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m2 basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, or approximately 50 and 2 times, respectively, the single MRHD of 6 mg administered subcutaneously on a mg/m2 basis. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 80 times the single MRHD of 6 mg administered subcutaneously on a mg/m2 basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 100 times the single MRHD of 6 mg administered subcutaneously on a mg/m2 basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 160 times the single MRHD of 6 mg administered subcutaneously on a mg/m2 basis. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.3 Nursing Mothers Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Injection. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. IMITREX Injection is not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated IMITREX Nasal Spray (5 to 20 mg) in 1,248 pediatric migraineurs 12 to 17 years of age who treated a single attack. The trials did not establish the efficacy of IMITREX Nasal Spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral IMITREX (25 to 100 mg) in pediatric patients 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral IMITREX compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients. Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral IMITREX; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal IMITREX are not presently available. 8.5 Geriatric Use Clinical trials of IMITREX Injection did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX Injection [see Warnings and Precautions (5.1)]. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 OVERDOSAGE Coronary vasospasm was observed after intravenous administration of IMITREX Injection [see Contraindications (4)]. Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis. The elimination half-life of sumatriptan is about 2 hours [see Clinical Pharmacology (12.3)]; therefore, monitoring of patients after overdose with IMITREX Injection should continue for at least 10 hours or while symptoms or signs persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan. 11 DESCRIPTION IMITREX Injection contains sumatriptan succinate, a selective 5-HT1B/1D receptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole 5-methanesulfonamide succinate (1:1), and it has the following structure: structural formula The empirical formula is C14H21N3O2SC4H6O4, representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline. IMITREX Injection is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of IMITREX Injection 8 mg/mL solution contains 4 mg of sumatriptan (base) as the succinate salt and 3.8 mg of sodium chloride, USP in Water for Injection, USP. Each 0.5 mL of IMITREX Injection 12 mg/mL solution contains 6 mg of sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range of both solutions is approximately 4.2 to 5.3. The osmolality of both injections is 291 mOsmol. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine and cluster headaches through agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. 12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [see Warnings and Precautions (5.8)]. Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan’s development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate. 12.3 Pharmacokinetics Absorption and Bioavailability The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97%  16% of that obtained following intravenous injection. After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24  6 years, weight: 70 kg), the maximum serum concentration (Cmax) of sumatriptan was (mean  standard deviation) 74  15 ng/mL and the time to peak concentration (Tmax) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected subcutaneously in the thigh gave a Cmax of 61  15 ng/mL by manual injection versus 52  15 ng/mL by autoinjector techniques. The Tmax or amount absorbed was not significantly altered by either the site or technique of injection. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50  8 liters and the distribution half-life was 15  2 minutes. Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38%  7% as the IAA metabolite. Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194  149 mL/min and the terminal half-life was 115  19 minutes. Specific Populations Age The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Hepatic Impairment The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of IMITREX Injection in this population is contraindicated [see Contraindications (4)]. Race The systemic clearance and Cmax of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Drug Interaction Studies Monoamine Oxidase-A Inhibitors In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half- life. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat in which sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the highest dose in rat was Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reduced from 360 mg/kg/day during Week 21). The highest dose to mice and rats was approximately 130 and 260 times the single MRHD of 6 mg administered subcutaneously on a mg/m2 basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration. Mutagenesis Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays. Impairment of Fertility When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day or approximately 100 times the single human dose of 6 mg on a mg/m2 basis. When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both. 13.2 Animal Toxicology and/or Pharmacology Corneal Opacities Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; however, the relative plasma exposure at the lowest dose tested was approximately 3 times the human exposure after a 6-mg subcutaneous dose. 14 CLINICAL STUDIES 14.1 Migraine In controlled clinical trials enrolling more than 1,000 patients during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3, onset of relief began as early as 10 minutes following a 6-mg IMITREX Injection. Lower doses of IMITREX Injection may also prove effective, although the proportion of patients obtaining adequate relief was decreased and the latency to that relief is greater with lower doses. In Study 1, 6 different doses of IMITREX Injection (n = 30 each group) were compared with placebo (n = 62), in a single-attack, parallel-group design, the dose-response relationship was found to be as shown in Table 2. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2. Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by IMITREX Dose in Study 1 Dose of IMITREX Injection Percent Patients with Reliefa Adverse Reactions Incidence (%) at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours Placebo 1 mg 2 mg 3 mg 4 mg 6 mg 8 mg 5 10 7 17 13 10 23 15 40 23 47 37 63 57 24 43 57 57 50 73 80 21 40 43 60 57 70 83 55 63 63 77 80 83 93 a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication. In 2 randomized, placebo-controlled clinical trials of IMITREX Injection 6 mg in 1,104 patients with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 10 minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe to mild or no headache, was achieved in 70% of the patients within 1 hour of a single 6-mg subcutaneous dose of IMITREX Injection. Approximately 82% and 65% of patients treated with IMITREX 6 mg had headache relief and were pain free within 2 hours, respectively. Table 3 shows the 1- and 2-hour efficacy results for IMITREX Injection 6 mg in Studies 2 and 3. Table 3. Proportion of Patients with Pain Relief and Relief of Migraine Symptoms after 1 and 2 Hours of Treatment in Studies 2 and 3 1-Hour Data Study 2 Study 3 Placebo (n = 190) IMITREX 6 mg (n = 384) Placebo (n = 180) IMITREX 6 mg (n = 350) Patients with pain relief (grade 0/1) Patients with no pain Patients without nausea Patients without photophobia Patients with little or no clinical disabilityb 18% 5% 48% 23% 34% 70%a 48%a 73%a 56%a 76%a 26% 13% 50% 25% 34% 70%a 49%a 73%a 58%a 76%a Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2-Hour Data Study 2 Study 3 Placeboc IMITREX 6 mgd Placeboc IMITREX 6 mgd Patients with pain relief (grade 0/1) Patients with no pain Patients without nausea Patients without photophobia Patients with little or no clinical disabilityb 31% 11% 56% 31% 42% 81%a 63%a 82%a 72%a 85%a 39% 19% 63% 35% 49% 82%a 65%a 81%a 71%a 84%a a P<0.05 versus placebo. b A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. c Includes patients that may have received an additional placebo injection 1 hour after the initial injection. d Includes patients that may have received an additional 6 mg of IMITREX Injection 1 hour after the initial injection. IMITREX Injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. Similar efficacy was seen when patients self-administered IMITREX Injection using the IMITREX STATdose Pen. The efficacy of IMITREX Injection was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the patient, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers). 14.2 Cluster Headache The efficacy of IMITREX Injection in the acute treatment of cluster headache was demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period crossover trials (Studies 4 and 5). Patients 21 to 65 years of age were enrolled and were instructed to treat a moderate to very severe headache within 10 minutes of onset. Headache relief was defined as a reduction in headache severity to mild or no pain. In both trials, the proportion of individuals gaining relief at 10 or 15 minutes was significantly greater among patients receiving 6 mg of IMITREX Injection compared with those who received placebo (see Table 4). Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4. Proportion of Patients with Cluster Headache Relief by Time in Studies 4 and 5 Study 4 Study 5 Placebo (n = 39) IMITREX 6 mg (n = 39) Placebo (n = 88) IMITREX 6 mg (n = 92) Patients with pain relief (no/mild) 5 Minutes post-injection 10 Minutes post-injection 15 Minutes post-injection 8% 10% 26% 21% 49%a 74%a 7% 25% 35% 23%a 49%a 75%a a P<0.05. (n = Number of headaches treated.) An estimate of the cumulative probability of a patient with a cluster headache obtaining relief after being treated with either IMITREX Injection or placebo is presented in Figure 1. Figure 1. Time to Relief of Cluster Headache from Time of Injectiona graph a The figure uses Kaplan-Meier (product limit) Survivorship Plot. Patients taking rescue medication were censored at 15 minutes. The plot was constructed with data from patients who either experienced relief or did not require (request) rescue medication within a period of 2 hours following treatment. As a consequence, the data in the plot are derived from only a subset of the 258 headaches treated (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 headaches treated with IMITREX Injection). Other data suggest that treatment with IMITREX Injection is not associated with an increase in early recurrence of headache and has little effect on the incidence of later-occurring headaches (i.e., those occurring after 2, but before 18 or 24 hours). Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 HOW SUPPLIED/STORAGE AND HANDLING IMITREX Injection contains sumatriptan (base) as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution as follows: Prefilled Syringe and/or Autoinjector Pen: Each pack contains a Patient Information and Patient Instructions for Use leaflet.  IMITREX STATdose System®, 4 mg, containing 1 IMITREX STATdose Pen, 2 prefilled single-dose syringe cartridges, and 1 carrying case (NDC 0173-0739-00).  IMITREX STATdose System, 6 mg, containing 1 IMITREX STATdose Pen, 2 prefilled single-dose syringe cartridges, and 1 carrying case (NDC 0173-0479-00).  Two 4-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose System (NDC 0173-0739-02).  Two 6-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose System (NDC 0173-0478-00). Single-Dose Vial:  IMITREX Injection single-dose vial (6 mg/0.5 mL) in cartons containing 5 vials (NDC 0173 0449-02). Store between 2° and 30°C (36° and 86°F). Protect from light. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events Inform patients that IMITREX Injection may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech, and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)]. Anaphylactic/Anaphylactoid Reactions Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX Injection. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications (4), Warnings and Precautions (5.9)]. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concomitant Use with Other Triptans or Ergot Medications Inform patients that use of IMITREX Injection within 24 hours of another triptan or an ergot- type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications (4), Drug Interactions (7.1, 7.3)]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome with the use of IMITREX Injection or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7), Drug Interactions (7.4)]. Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)]. Pregnancy Inform patients that IMITREX Injection should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. Nursing Mothers Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.3)]. Ability to Perform Complex Tasks Treatment with IMITREX Injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of IMITREX Injection. How to Use IMITREX Injection Provide patients instruction on the proper use of IMITREX Injection if they are able to self- administer IMITREX Injection in medically unsupervised situations. Inform patients that the needle in the IMITREX STATdose Pen penetrates approximately 1/4 of an inch (5 to 6 mm). Inform patients that the injection is intended to be given subcutaneously and intramuscular or intravascular delivery should be avoided. Instruct patients to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. IMITREX, IMITREX STATdose Pen, and IMITREX STATdose System are registered trademarks of the GSK group of companies. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo Research Triangle Park, NC 27709 ©Year, the GSK group of companies. All rights reserved. IMJ:xPI Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patient Information IMITREX® (IM-i-trex) (sumatriptan succinate) Injection Read this Patient Information before you start taking IMITREX and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information I should know about IMITREX? IMITREX can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. Stop taking IMITREX and get emergency medical help right away if you have any of the following symptoms of a heart attack:  discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back  severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw  pain or discomfort in your arms, back, neck, jaw, or stomach  shortness of breath with or without chest discomfort  breaking out in a cold sweat  nausea or vomiting  feeling lightheaded IMITREX is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you:  have high blood pressure  have high cholesterol levels  smoke  are overweight  have diabetes  have a family history of heart disease What is IMITREX? IMITREX Injection is a prescription medicine used to treat acute migraine headaches with or without aura and acute cluster headaches in adults who have been diagnosed with migraine or cluster headaches. IMITREX is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda IMITREX is not used to prevent or decrease the number of migraine or cluster headaches you have. It is not known if IMITREX is safe and effective in children under 18 years of age. Who should not take IMITREX? Do not take IMITREX if you have:  heart problems or a history of heart problems  narrowing of blood vessels to your legs, arms, stomach, or kidneys (peripheral vascular disease)  uncontrolled high blood pressure  severe liver problems  hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.  had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation  taken any of the following medicines in the last 24 hours:  almotriptan (AXERT®)  eletriptan (RELPAX®)  frovatriptan (FROVA®)  naratriptan (AMERGE®)  rizatriptan (MAXALT®, MAXALT-MLT®)  sumatriptan and naproxen (TREXIMET®)  ergotamines (CAFERGOT®, ERGOMAR®, MIGERGOT®)  dihydroergotamine (D.H.E. 45®, MIGRANAL®) Ask your healthcare provider if you are not sure if your medicine is listed above.  an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of this leaflet for a complete list of ingredients in IMITREX. What should I tell my healthcare provider before taking IMITREX? Before you take IMITREX, tell your healthcare provider about all of your medical conditions, including if you:  have high blood pressure  have high cholesterol  have diabetes  smoke  are overweight  have heart problems or family history of heart problems or stroke  have kidney problems  have liver problems Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  have had epilepsy or seizures  are not using effective birth control  become pregnant while taking IMITREX  are breastfeeding or plan to breastfeed. IMITREX passes into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take IMITREX. Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. IMITREX and certain other medicines can affect each other, causing serious side effects. Especially tell your healthcare provider if you take anti-depressant medicines called:  selective serotonin reuptake inhibitors (SSRIs)  serotonin norepinephrine reuptake inhibitors (SNRIs)  tricyclic antidepressants (TCAs)  monoamine oxidase inhibitors (MAOIs) Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. How should I take IMITREX?  Certain people should take their first dose of IMITREX in their healthcare provider’s office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting.  Use IMITREX exactly as your healthcare provider tells you to use it.  Your healthcare provider may change your dose. Do not change your dose without first talking with your healthcare provider.  For adults, the usual dose is a single injection given just below the skin.  You should give an injection as soon as the symptoms of your headache start, but it may be given at any time during a migraine or cluster headache attack.  If you did not get any relief after the first injection, do not give a second injection without first talking with your healthcare provider.  If your headache comes back or you only get some relief after your first injection, you can take a second injection 1 hour after the first injection, but not sooner.  Do not take more than 12 mg in a 24-hour period. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  If you use too much IMITREX, call your healthcare provider or go to the nearest hospital emergency room right away.  You should write down when you have headaches and when you take IMITREX so you can talk with your healthcare provider about how IMITREX is working for you. What should I avoid while taking IMITREX? IMITREX can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert. What are the possible side effects of IMITREX? IMITREX may cause serious side effects. See “What is the most important information I should know about IMITREX?” These serious side effects include:  changes in color or sensation in your fingers and toes (Raynaud’s syndrome)  stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include:  sudden or severe stomach pain  stomach pain after meals  weight loss  nausea or vomiting  constipation or diarrhea  bloody diarrhea  fever  problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include:  cramping and pain in your legs or hips  feeling of heaviness or tightness in your leg muscles  burning or aching pain in your feet or toes while resting  numbness, tingling, or weakness in your legs  cold feeling or color changes in 1 or both legs or feet  hives (itchy bumps); swelling of your tongue, mouth, or throat  medication overuse headaches. Some people who use too many IMITREX injections may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with IMITREX. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using IMITREX, especially if IMITREX is used with anti-depressant medicines called SSRIs or SNRIs. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome:  mental changes such as seeing things that are not there (hallucinations), agitation, or coma  fast heartbeat  changes in blood pressure  high body temperature  tight muscles  trouble walking  seizures. Seizures have happened in people taking IMITREX who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take IMITREX. The most common side effects of IMITREX Injection include:  pain or redness at your injection site  tingling or numbness in your fingers or toes  dizziness  warm, hot, burning feeling to your face (flushing)  discomfort or stiffness in your neck  feeling weak, drowsy, or tired Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of IMITREX. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store IMITREX Injection?  Store IMITREX between 36°F to 86°F (2°C to 30°C).  Store your medicine away from light.  Keep your medicine in the packaging or carrying case provided with it. Keep IMITREX and all medicines out of the reach of children. General information about the safe and effective use of IMITREX Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use IMITREX for a condition for which it was not prescribed. Do not give IMITREX to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about IMITREX. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about IMITREX that is written for healthcare professionals. For more information, go to www.gsk.com or call 1-888-825-5249. What are the ingredients in IMITREX Injection? Active ingredient: sumatriptan succinate Inactive ingredients: sodium chloride, water for injection This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. IMITREX and AMERGE are registered trademarks of the GSK group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products. company logo Research Triangle Park, NC 27709 ©Year, the GSK group of companies. All rights reserved. Month Year IMJ:xPPI Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda u s a g e illustration Read this Patient Instructions for Use before you start to use the IMITREX STATdose System. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about IMITREX Injection when you start taking it and at regular checkups. Keep the IMITREX STATdose System out of the reach of children. Before you use the IMITREX STATdose System When you first open the IMITREX STATdose System box, the Cartridge Pack and the IMITREX STATdose Pen® are already in the Carrying Case for your convenience. 2 The grey and blue Carrying Case is used for 3 storing the unloaded Pen and the Cartridge 4 Pack when they are not being used. 5 The Cartridge Pack holds 2 individually 6 sealed Syringe Cartridges. Each Syringe 7 Cartridge holds 1 dose of IMITREX® 8 (sumatriptan succinate) Injection. The 9 Cartridge Pack for the 4-mg strength of this usage illustration Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 11 medicine is yellow, and the Cartridge Pack for 12 the 6-mg strength is blue (as shown). Refill 13 Cartridge Packs are available. 14 The grey and blue Pen is used to automatically inject 1 dose of medicine from a 15 Syringe Cartridge. Do not touch the Blue Button until you have pressed the Pen 16 against your skin to give a dose. If you press it at any other time, you might lose a 17 dose. The Safety Catch keeps the Pen from accidentally firing until you are ready. 18 The Pen will only work when you slide the grey part of the barrel down to the blue 19 part. Always check to make sure that the white Priming Rod is not sticking out from 20 the end of the Pen (as shown in Figure B) before you load a new Syringe Cartridge. 21 If it is sticking out, you will lose that dose. 22 How to load the IMITREX STATdose Pen 23 Do not load the Pen until you are ready to give yourself an injection. 24 Do not touch the Blue Button on top of the Pen (see Figure A) 25 while you are loading the Pen. 34 1. Open the lid of the Carrying Case. The tamper 35 evident seals over the 2 Syringe Cartridges are 36 labeled “A” and “B” (see Figure A inset). 37 Always use the Syringe Cartridge marked “A” 38 before the one marked “B” to help you keep 39 track of your doses. Do not use if either seal 40 is broken or missing when you first open 41 the Carrying Case. 28 Figure A 29 42 2. Tear off one of the tamper-evident seals (see 43 Figure A). Throw away the seal. Open the lid 30 44 over the Syringe Cartridge. 45 3. Hold the Pen by the ridges at the top. Take 46 the Pen out of the Carrying Case (see Figure 47 B). 48 Check to make sure the white Priming Rod is 49 not sticking out from the lower end of the Pen 50 (see Figure B inset). If it is sticking out, put 51 the Pen back into the Carrying Case and press 32 Figure B 52 down firmly until you feel it click. Take the Pen 33 53 out of the Carrying Case. usa ge illustration usage illustration Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 59 4. Put the Pen in the Cartridge Pack. Turn it to 60 the right (clockwise) until it will not turn any 61 more (about half a turn) (see Figure C). 62 63 64 65 55 Figure C 66 67 5. Hold the loaded Pen by the ridges and pull it 68 straight out (see Figure D). You may need 69 to pull hard on the Pen, but this is normal. Do 70 not press the Blue Button yet. 57 Figure D 7158 The Pen is now ready to use. Do not put the loaded Pen back into the Carrying 72 Case because that will damage the needle. usage illustration usage illustration 73 How to use the IMITREX STATdose Pen to take your medicine 74 Before injecting your medicine, choose an area with a fatty tissue layer (see Figure 75 E or Figure F). Ask your healthcare provider if you have a question about where to 76 inject your medicine. 77 To prepare the area of skin where IMITREX is to be injected, wipe the injection site 78 with an alcohol swab. Do not touch this area again before giving the injection. usage illustration Figure E or Figure F Figure G 967 6. Without pushing the Blue Button, press the loaded Pen firmly against the skin so 968 that the grey barrel slides down toward the blue section that holds the Syringe Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 969 Cartridge (see Figure D). (This releases the Safety Catch that keeps the Pen 970 from firing by mistake until you are ready.) 971 7. Push the Blue Button. Hold the Pen still for at least 5 seconds. If the Pen is 972 taken away from the skin too soon, not all the medicine will come out. 973 8. After 5 seconds, carefully take the Pen away from your skin. The needle will be 974 showing (see Figure G). Do not touch the needle. 975 How to unload the IMITREX STATdose Pen after taking your medicine 976 Right after you take a dose with the Pen, you need to return the used Syringe 977 Cartridge to the Cartridge Pack. usage illustration Figure I Figure J 978 9. Push the Pen down into the empty side of the Cartridge Pack as far as it will go 979 (see Figure H). 980 10.Turn the Pen to the left (counterclockwise) about half a turn until it is released 981 from the Syringe Cartridge (see Figure I). 982 11.Pull the empty Pen out of the Cartridge Pack (see Figure J). 983 Because the Pen has now been used, the white Priming Rod will stick out from the 984 lower end of the Pen (see Figure J). 985 12.Close the Cartridge Pack lid over the used Syringe Cartridge. When the used 986 Syringe Cartridges are inserted correctly, the Cartridge Pack is a disposable, 987 protective case to help you avoid needle sticks and use the syringes correctly. 988 13.Put the Pen back into the Carrying Case and press it down firmly until you feel it 989 click. Close the Carrying Case lid. This gets the Pen ready for the next use. 990 If the lid will not close, push the Pen down until you feel it click. Then close the 991 lid. 992 How to take out a used Cartridge Pack Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 993 After both Syringe Cartridges have been used, take the Cartridge Pack out of the 994 Carrying Case. Never reuse or recycle a Syringe Cartridge. usage illustrationusage illustration Figure K Figure L 995 14.Open the Carrying Case lid. 996 15.Hold the Carrying Case with one hand and press the 2 buttons on either side of 997 the Carrying Case (see Figure K). 998 16.Gently pull out the Cartridge Pack with the other hand (see Figure L). 999 17.Throw away the Cartridge Pack or dispose of it as instructed by your healthcare 1000 provider. There may be special state and local laws for disposing of used needles 1001 and syringes. Always keep out of the reach of children. 1002 How to insert a new Cartridge Pack usage illustration Figure M Figure N Figure O 1004 18.Take the new Cartridge Pack out of its box. Do not take off the 1005 tamper-evident seals (see Figure M). 1006 19.Put the Cartridge Pack in the Carrying Case. Slide it down smoothly (see Figure 1007 N). 1008 20.The Cartridge Pack will click into place when the 2 buttons show through the 1009 holes in the Carrying Case (see Figure O). Close the lid. 1010 1011 This Patient Information and Instructions for Use has been approved by the U.S. 1012 Food and Drug Administration. Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1013 1014 AMERGE, IMITREX, IMITREX STATdose System, and IMITREX STATdose Pen are 1015 registered trademarks of the GSK group of companies. The other brands listed are 1016 trademarks of their respective owners and are not trademarks of the GSK group of 1017 companies. The makers of these brands are not affiliated with and do not endorse 1018 the GSK group of companies or its products. 1019 1020 1021 1022 GlaxoSmithKline 1023 Research Triangle Park, NC 27709 1024 1025 ©Year, the GSK group of companies. All rights reserved. 1026 1027 Month Year 1028 IMJ:xPIL Reference ID: 3777908 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:41.495250	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020080s048lbl.pdf', 'application_number': 20080, 'submission_type': 'SUPPL ', 'submission_number': 48}
12,190	Hepatotoxicity Labeling -062602 1 JANSSEN PHARMACEUTICA PRODUCTS, L.P. SPORANOX  (ITRACONAZOLE) CAPSULES Congestive Heart Failure SPORANOX  (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) Drug Interactions: Coadministration of cisapride, pimozide, quinidine, or dofetilide with SPORANOX® (itraconazole) Capsules, Injection or Oral Solution is contraindicated. SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, or quinidine, concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information. DESCRIPTION SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 2 (insert structure) (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5- one mixture with (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2S,4R)-2-(2,4-dichlorophenyl)-2- (1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2- 1,2,4-triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5- one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n- octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are gelatin, hydroxypropyl methylcellulose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.) The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 3 The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below: 50 mg (fed) 100 mg (fed) 100 mg (fasted) 200 mg (fed) Cmax (ng/mL) 45 ± 16* 132 ± 67 38 ± 20 289 ± 100 Tmax (hours) 3.2 ± 1.3 4.0 ± 1.1 3.3 ± 1.0 4.7 ± 1.4 AUC0-∞ (ng·h/mL) 567 ± 264 1899 ± 838 722 ± 289 5211 ± 2116 mean + standard deviation Doubling the SPORANOX® dose results in approximately a three-fold increase in the itraconazole plasma concentrations. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX® Capsules with or without a full meal: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 4 Itraconazole Hydroxyitraconazole Fed Fasted Fed Fasted Cmax (ng/mL) 239 ± 85 140 ± 65 397 ± 103 286 ± 101 Tmax (hours) 4.5 ± 1.1 3.9 ± 1.0 5.1 ± 1.6 4.5 ± 1.1 AUC0-∞ (ng·h/mL) 3423 ± 1154 2094 ± 905 7978 ± 2648 5191 ± 2489 t1/2 (hours) 21 ± 5 21 ± 7 12 ± 3 12 ± 3 mean ± standard deviation Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX® Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX® Capsules were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX® Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX® Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When SPORANOX® Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 5 Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX® Capsules b.i.d.(with a full meal) for 15 days: Itraconazole Hydroxyitraconazole Cmax (ng/mL) 2282 ± 514 3488 ± 742 Cmin (ng/mL) 1855 ± 535 3349 ± 761 Tmax (hours) 4.6 ± 1.8 3.4 ± 3.4 AUC0-12 h (ng·h/mL) 22569 ± 5375 38572 ± 8450 t1/2 (hours) 64 ± 32 56 ± 24 mean ± standard deviation The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.) Special Populations: Renal Insufficiency: A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 6 impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. x 1.73 m2, the bioavailability was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Hepatic Insufficiency: A pharmacokinetic study using a single 100-mg dose of itraconazole (one 100-mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX Capsules, SPORANOX should be discontinued. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post- marketing Experience for more information.) MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 7 Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum and Blastomyces dermatitidis. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species. Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 8 Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 9 (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non- concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non- concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, “single-patient- use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 10 Onychomycosis of the toenail: Analyses were conducted on data from three double- blind, placebo-controlled studies (N=214 total; 110 given SPORANOX Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX Capsules b.i.d., followed by a 3-week period without SPORANOX, which was followed by a second 1-week pulse of 200 mg of SPORANOX Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS Congestive Heart Failure: SPORANOX (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Post-marketing Experience.) Drug Interactions: Concomitant administration of SPORANOX (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 11 of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, pimozide, quinidine, dofetilide, and triazolam are contraindicated with SPORANOX. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOX should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX to patients with hypersensitivity to other azoles. WARNINGS SPORANOX (itraconazole) Capsules and SPORANOX Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Hepatic Effects: SPORANOX  has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX  use or reinstitution of treatment with SPORANOX  is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 12 Cardiac Disease: SPORANOX Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX Capsules, discontinue administration. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS General: Rare cases of serious hepatotoxicity have been observed with Sporanox treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 13 abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Sporanox. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. If neuropathy occurs that may be attributable to Sporanox capsules, the treatment should be discontinued. SPORANOX (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Information for Patients: • The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used interchangeably with SPORANOX® Oral Solution. • Instruct patients to take SPORANOX Capsules with a full meal. • Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX administration, they should discontinue SPORANOX and contact their healthcare provider immediately. • Instruct patients to stop Sporanox treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 14 • Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1 below and the following drug class subheadings that follow): 1. SPORANOX may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. 2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX may not be effective in patients concomitantly taking SPORANOX and one of these drugs. Therefore, administration of these drugs with SPORANOX is not recommended. 3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 15 Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by SPORANOX 1 Drug plasma concentration increased by itraconazole Antiarrhythmics digoxin, dofetilide2, quinidine2 Anticonvulsants carbamazepine Antimycobacterials rifabutin Antineoplastics busulfan, docetaxel, vinca alkaloids Antipsychotics pimozide2 Benzodiazepines alprazolam, diazepam, midazolam,2,3 triazolam2 Calcium Channel Blockers dihydropyridines, verapamil Gastrointestinal Motility Agents cisapride2 HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2 Immunosuppressants cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics oral hypoglycemics Protease Inhibitors indinavir, ritonavir, saquinavir Other alfentanil, buspirone, methylprednisolone, trimetrexate, warfarin Decrease plasma concentration of itraconazole Anticonvulsants carbamazepine, phenobarbital, phenytoin Antimycobacterials isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors Non-nucleoside Reverse Transcriptase Inhibitors nevirapine Increase plasma concentration of itraconazole Macrolide Antibiotics clarithromycin, erythromycin Protease Inhibitors indinavir, ritonavir 1This list is not all-inclusive. 2Contraindicated with SPORANOX based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) 3For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 16 administration of SPORANOX and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Concomitant administration of digoxin and SPORANOX has led to increased plasma concentrations of digoxin. Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and carbamazepine may inhibit the metabolism of carbamazepine. Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOX may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 17 Benzodiazepines: Concomitant administration of SPORANOX and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged. Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX Capsules. In a clinical study, when SPORANOX Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. Gastrointestinal Motility Agents: Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 18 HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOX and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied. Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 19 Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined. Protease Inhibitors: Concomitant administration of SPORANOX and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX and protease inhibitors must be given concomitantly. Other: • In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX may increase plasma concentrations of alfentanil. • Human pharmacokinetic data suggest that concomitant administration of SPORANOX and buspirone results in significant increases in plasma concentrations of buspirone. • SPORANOX may inhibit the metabolism of methylprednisolone. • In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and trimetrexate may inhibit the metabolism of trimetrexate. • SPORANOX enhances the anticoagulant effect of coumarin-like drugs, such as warfarin. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 20 itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOX therapy and for 2 months following the end of treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 21 Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX have not been established in pediatric patients. No pharmacokinetic data on SPORANOX Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. ADVERSE REACTIONS SPORANOX has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: General and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 22 in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 23 Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea 11 Vomiting 5 Diarrhea 3 Abdominal Pain 2 Anorexia 1 Body as a Whole Edema 4 Fatigue 3 Fever 3 Malaise 1 Skin and Appendages Rash 9 Pruritus 3 Central/Peripheral Nervous System Headache 4 Dizziness 2 Psychiatric Libido Decreased 1 Somnolence 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 *Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 24 Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 25 Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Post-marketing Experience Worldwide post-marketing experiences with the use of SPORANOX include adverse events of gastrointestinal origin, such as dyspepsia, nausea, vomiting, diarrhea, abdominal pain and constipation. Other reported adverse events include peripheral edema, congestive heart failure and pulmonary edema, headache, dizziness, peripheral neuropathy, menstrual disorders, reversible increases in hepatic enzymes, hepatitis, liver failure, hypokalemia, hypertriglyceridemia, alopecia, allergic reactions (such as pruritus, rash, urticaria, angioedema, anaphylaxis), Stevens-Johnson syndrome, and neutropenia. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information). OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX (itraconazole) Oral Solution or up to 3000 mg of SPORANOX (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 26 DOSAGE AND ADMINISTRATION SPORANOX (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX Capsules is a different preparation than SPORANOX Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously. • IV Injection: the recommended intravenous dose is 200 mg b.i.d. for four consecutive doses, followed by 200 mg once daily thereafter. Each intravenous dose should be infused over 1 hour. The safety and efficacy of SPORANOX Injection administered for greater than 14 days is not known. See complete prescribing information for SPORANOX (itraconazole) Injection. • Capsules: although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX Capsules and SPORANOX Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 27 Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX. HOW SUPPLIED SPORANOX (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 x 10 capsules (NDC 50458-290-01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs x 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children.  Janssen 2001 7501618 U.S. Patent Nos. 4,267,179; 5,633,015 Revised June 2002 Distributed by: JANSSEN PHARMACEUTICA PRODUCTS, L.P. Titusville, New Jersey 08560, USA Capsule contents manufactured by: JANSSEN JANSSEN PHARMACEUTICA N.V. PHARMACEUTICA Beerse, Belgium PRODUCTS, L.P. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Patient Information 1 SPORANOX® 2 (itraconazole) Capsules 3 4 This summary contains important information about SPORANOX (SPOR-ah-nox). 5 This information is for patients who have been prescribed SPORANOX to treat fungal nail 6 infections. If your doctor prescribed SPORANOX for medical problems other than 7 fungal nail infections, ask your doctor if there is any information in this summary 8 that does not apply to you. Read this information carefully each time you start to use 9 SPORANOX. This information does not take the place of discussion between you and 10 your doctor. Only your doctor can decide if SPORANOX is the right treatment for you. 11 If you do not understand some of this information or have any questions, talk with your 12 doctor or pharmacist. 13 14 What Is The Most Important Information I Should Know About SPORANOX? 15 16 SPORANOX is used to treat fungal nail infections. However, SPORANOX is not for 17 everyone. Do not take SPORANOX for fungal nail infections if you have had heart 18 failure, including congestive heart failure. You should not take SPORANOX if you 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI are taking certain medicines that could lead to serious or life-threatening medical 20 problems. (See “Who Should Not Take SPORANOX?” below). 21 22 If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor 23 if it is safe for you to take SPORANOX. 24 25 What Happens If I Have A Fungal Nail Infection? 26 27 Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus 28 infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If 29 not treated, the fungus may spread under the nail towards the cuticle. If the fungus 30 spreads, more of the nail may change color, may become thick or brittle, and the tip of the 31 nail may become raised. In some patients, this can cause pain and discomfort. 32 33 What Is SPORANOX? 34 35 SPORANOX is a prescription medicine used to treat fungal infections of the toenails and 36 fingernails. It is also used to treat some types of fungal infections in other areas of your 37 body. We do not know if SPORANOX works in children with fungal nail infections or if 38 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI it is safe for children to take. 39 40 SPORANOX comes in the form of capsules and liquid (oral solution). The capsule and 41 liquid forms work differently, so you should not use one in place of the other. This Patient 42 Information discusses only the capsule form of SPORANOX. You will get these capsules 43 in a medicine bottle or a SPORANOX PulsePak®. The PulsePak contains 28 capsules for 44 treatment of your fungal nail infection. 45 46 SPORANOX goes into your bloodstream and travels to the source of the infection 47 underneath the nail so that it can fight the infection there. Improved nails may not be 48 obvious for several months after the treatment period is finished because it usually takes 49 about 6 months to grow a new fingernail and 12 months to grow a new toenail. 50 51 Who Should Not Take SPORANOX? 52 53 SPORANOX is not for everyone. Your doctor will decide if SPORANOX is the right 54 treatment for you. Some patients should not take SPORANOX because they may have 55 certain health problems or may be taking certain medicines that could lead to serious 56 or life-threatening medical problems. 57 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 58 Tell your doctor and pharmacist the name of all the prescription and non-prescription 59 medicines you are taking, including dietary supplements and herbal remedies. Also tell 60 your doctor about any other medical conditions you have had, especially heart, lung, liver 61 or kidney conditions. 62 63 Never take SPORANOX if you: 64 65 • have had heart failure, including congestive heart failure. 66 67 • are taking any of the medicines listed below. Dangerous or even life-threatening 68 abnormal heartbeats could result: 69 • quinidine (such as Cardioquin®, Quinaglute®, Quinidex®) 70 • dofetilide (such as Tikosyn) 71 • cisapride (such as Propulsid®) 72 • pimozide (such as Orap®) 73 74 • are taking any of the following medicines: 75 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI • lovastatin (such as Mevacor®, Advicor) 76 • simvastatin (such as Zocor®) 77 • triazolam (such as Halcion®) 78 • midazolam (such as Versed®) 79 80 • have ever had an allergic reaction to itraconazole or any of the other ingredients in 81 SPORANOX Capsules. Ask your doctor or pharmacist for a list of these 82 ingredients. 83 84 What Should I Know About SPORANOX and Pregnancy or Breast Feeding? 85 86 Never take SPORANOX if you have a fungal nail infection and are pregnant or planning 87 to become pregnant within 2 months after you have finished your treatment. 88 89 If you are able to become pregnant, you should use effective birth control during 90 SPORANOX treatment and for 2 months after finishing treatment. Ask your doctor about 91 effective types of birth control. 92 93 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI If you are breast-feeding, talk with your doctor about whether you should take Sporanox. 94 95 How Should I Take SPORANOX? 96 97 Always take SPORANOX Capsules during or right after a full meal. 98 99 Your doctor will decide the right dose for you. Depending on your infection, you will 100 take SPORANOX once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing 101 schedule. You will receive either a bottle of capsules or a PulsePak. Do not skip any 102 doses. Be sure to finish all your SPORANOX as prescribed by your doctor. 103 If you have ever had liver problems, your doctor should do a blood test to check your 104 105 condition. If you haven’t had liver problems, your doctor may recommend blood tests to 106 107 check the condition of your liver because patients taking SPORANOX can 108 109 develop liver problems. 110 111 If you forget to take or miss doses of SPORANOX, ask your doctor what you should do 112 with the missed doses. 113 114 The SPORANOX PulsePak 115 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 116 If you use the PulsePak, you will take SPORANOX for 1 week and then take no 117 SPORANOX for the next 3 weeks before repeating the 1-week treatment. This is called 118 “pulse dosing.” The SPORANOX PulsePak contains enough medicine for one “pulse” (1 119 week of treatment). 120 121 The SPORANOX PulsePak comes with special instructions. It contains 7 pouches—one 122 for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at 123 the back of the card, fold it back along the dashed line and peel away the backing so that 124 you can remove 2 capsules. 125 126 • Take 2 capsules in the morning and 2 capsules in the evening. This means you 127 will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all 128 of the capsules in the PulsePak box. 129 130 • After you finish the PulsePak, do not take any SPORANOX for the next 3 weeks. 131 Even though you are not taking any capsules during this time, SPORANOX keeps 132 working inside your nails to help fight the fungal infection. 133 134 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI • You will need more than one “pulse” to treat your fungal nail infection. When 135 your doctor prescribes another pulse treatment, be sure to get your refill before the 136 end of week 4. 137 138 139 140 141 142 SPORANOX Pulse Dosing Take 2 SPORANOX capsules twice a day for 1 week Day1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 AM PM AM PM AM PM AM PM AM PM AM PM AM PM Week 1 // // // // // // // // // // // // // // This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Week 2 Week 3 Week 4 For the next 3 weeks, do not take any SPORANOX capsules. Remember to get a refill before the end of Week 4 when your doctor prescribes another PulsePak. 143 What Are the Possible Side Effects of SPORANOX? 144 145 The most common side effects that cause people to stop treatment either for a short time 146 or completely include: skin rash, high triglyceride test results, high liver test results, and 147 digestive system problems (such as nausea, bloating, and diarrhea). 148 149 Stop SPORANOX and call your doctor right away if you develop shortness of breath; 150 have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually 151 tired; cough up white or pink phlegm; or have unusual fast heartbeats. In rare cases, 152 patients taking SPORANOX could develop serious heart problems, and these could be 153 warning signs of heart failure. 154 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 155 Stop SPORANOX and call your doctor right away if you become unusually tired; lose 156 your appetite; or develop nausea or vomiting, a yellow color to your skin or eyes, or dark 157 colored urine or pale stools (bowel movements). In rare cases, patients taking 158 SPORANOX could develop serious liver problems and these could be warning signs. 159 160 Call your doctor right away if you develop tingling or numbness in your extremities 161 (hands or feet). 162 These are not all the side effects of SPORANOX. Your doctor or pharmacist can give you 163 a more complete list. 164 165 What Should I Do If I Take An Overdose of SPORANOX? 166 167 If you think you took too much SPORANOX, call your doctor or local poison control 168 center, or go to the nearest hospital emergency room right away. 169 170 How Should I Store SPORANOX? 171 172 Keep all medicines, including SPORANOX, out of the reach of children. 173 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 174 Store SPORANOX Capsules and the PulsePak at room temperature in a dry place away 175 from light. 176 177 General Advice About SPORANOX 178 179 Medicines are sometimes prescribed for conditions that are not mentioned in patient 180 information leaflets. Do not use SPORANOX for a condition for which it was not 181 prescribed. Do not give SPORANOX to other people, even if they have the same 182 symptoms you have. It may harm them. 183 184 This leaflet summarizes the most important information about SPORANOX. If you would 185 like more information, talk with your doctor. You can ask your doctor or pharmacist for 186 information about SPORANOX that is written for health professionals. 187 188 You can also call 1-800-JANSSEN or visit the SPORANOX Internet site at 189 www.sporanox.com and the Janssen Internet site at www.us.janssen.com. 190 191 This patient information has been approved by the U.S. Food and Drug Administration. 192 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 193 The following are registered trademarks of their respective manufacturers: 194 Mevacor® (Merck & Co., Inc.), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), 195 Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), 196 Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), 197 Propulsid® (Janssen Pharmaceutica Products, L.P.), and Orap® (Gate Pharmaceuticals) 198 199 Corporate Logo 200 © Janssen Pharmaceutica Products, L.P. 2002 201 Part Number 202 Printed in USA/ April, 2002. 203 204 205 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Renata Albrecht 7/17/02 12:42:21 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:41.647999	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20083s28s31lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 28}
12,192	Hepatotoxicity Labeling -062602 1 JANSSEN PHARMACEUTICA PRODUCTS, L.P. SPORANOX  (ITRACONAZOLE) CAPSULES Congestive Heart Failure SPORANOX  (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) Drug Interactions: Coadministration of cisapride, pimozide, quinidine, or dofetilide with SPORANOX® (itraconazole) Capsules, Injection or Oral Solution is contraindicated. SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, or quinidine, concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information. DESCRIPTION SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 2 (insert structure) (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5- one mixture with (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2S,4R)-2-(2,4-dichlorophenyl)-2- (1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2- 1,2,4-triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5- one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n- octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are gelatin, hydroxypropyl methylcellulose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.) The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 3 The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below: 50 mg (fed) 100 mg (fed) 100 mg (fasted) 200 mg (fed) Cmax (ng/mL) 45 ± 16* 132 ± 67 38 ± 20 289 ± 100 Tmax (hours) 3.2 ± 1.3 4.0 ± 1.1 3.3 ± 1.0 4.7 ± 1.4 AUC0-∞ (ng·h/mL) 567 ± 264 1899 ± 838 722 ± 289 5211 ± 2116 mean + standard deviation Doubling the SPORANOX® dose results in approximately a three-fold increase in the itraconazole plasma concentrations. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX® Capsules with or without a full meal: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 4 Itraconazole Hydroxyitraconazole Fed Fasted Fed Fasted Cmax (ng/mL) 239 ± 85 140 ± 65 397 ± 103 286 ± 101 Tmax (hours) 4.5 ± 1.1 3.9 ± 1.0 5.1 ± 1.6 4.5 ± 1.1 AUC0-∞ (ng·h/mL) 3423 ± 1154 2094 ± 905 7978 ± 2648 5191 ± 2489 t1/2 (hours) 21 ± 5 21 ± 7 12 ± 3 12 ± 3 mean ± standard deviation Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX® Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX® Capsules were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX® Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX® Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When SPORANOX® Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 5 Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX® Capsules b.i.d.(with a full meal) for 15 days: Itraconazole Hydroxyitraconazole Cmax (ng/mL) 2282 ± 514 3488 ± 742 Cmin (ng/mL) 1855 ± 535 3349 ± 761 Tmax (hours) 4.6 ± 1.8 3.4 ± 3.4 AUC0-12 h (ng·h/mL) 22569 ± 5375 38572 ± 8450 t1/2 (hours) 64 ± 32 56 ± 24 mean ± standard deviation The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.) Special Populations: Renal Insufficiency: A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 6 impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. x 1.73 m2, the bioavailability was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Hepatic Insufficiency: A pharmacokinetic study using a single 100-mg dose of itraconazole (one 100-mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX Capsules, SPORANOX should be discontinued. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post- marketing Experience for more information.) MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 7 Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum and Blastomyces dermatitidis. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species. Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 8 Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 9 (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non- concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non- concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, “single-patient- use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 10 Onychomycosis of the toenail: Analyses were conducted on data from three double- blind, placebo-controlled studies (N=214 total; 110 given SPORANOX Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX Capsules b.i.d., followed by a 3-week period without SPORANOX, which was followed by a second 1-week pulse of 200 mg of SPORANOX Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS Congestive Heart Failure: SPORANOX (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Post-marketing Experience.) Drug Interactions: Concomitant administration of SPORANOX (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 11 of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, pimozide, quinidine, dofetilide, and triazolam are contraindicated with SPORANOX. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOX should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX to patients with hypersensitivity to other azoles. WARNINGS SPORANOX (itraconazole) Capsules and SPORANOX Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Hepatic Effects: SPORANOX  has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX  use or reinstitution of treatment with SPORANOX  is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 12 Cardiac Disease: SPORANOX Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX Capsules, discontinue administration. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS General: Rare cases of serious hepatotoxicity have been observed with Sporanox treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 13 abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Sporanox. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. If neuropathy occurs that may be attributable to Sporanox capsules, the treatment should be discontinued. SPORANOX (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Information for Patients: • The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used interchangeably with SPORANOX® Oral Solution. • Instruct patients to take SPORANOX Capsules with a full meal. • Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX administration, they should discontinue SPORANOX and contact their healthcare provider immediately. • Instruct patients to stop Sporanox treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 14 • Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1 below and the following drug class subheadings that follow): 1. SPORANOX may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. 2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX may not be effective in patients concomitantly taking SPORANOX and one of these drugs. Therefore, administration of these drugs with SPORANOX is not recommended. 3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 15 Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by SPORANOX 1 Drug plasma concentration increased by itraconazole Antiarrhythmics digoxin, dofetilide2, quinidine2 Anticonvulsants carbamazepine Antimycobacterials rifabutin Antineoplastics busulfan, docetaxel, vinca alkaloids Antipsychotics pimozide2 Benzodiazepines alprazolam, diazepam, midazolam,2,3 triazolam2 Calcium Channel Blockers dihydropyridines, verapamil Gastrointestinal Motility Agents cisapride2 HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2 Immunosuppressants cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics oral hypoglycemics Protease Inhibitors indinavir, ritonavir, saquinavir Other alfentanil, buspirone, methylprednisolone, trimetrexate, warfarin Decrease plasma concentration of itraconazole Anticonvulsants carbamazepine, phenobarbital, phenytoin Antimycobacterials isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors Non-nucleoside Reverse Transcriptase Inhibitors nevirapine Increase plasma concentration of itraconazole Macrolide Antibiotics clarithromycin, erythromycin Protease Inhibitors indinavir, ritonavir 1This list is not all-inclusive. 2Contraindicated with SPORANOX based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) 3For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 16 administration of SPORANOX and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Concomitant administration of digoxin and SPORANOX has led to increased plasma concentrations of digoxin. Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and carbamazepine may inhibit the metabolism of carbamazepine. Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOX may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 17 Benzodiazepines: Concomitant administration of SPORANOX and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged. Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX Capsules. In a clinical study, when SPORANOX Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. Gastrointestinal Motility Agents: Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 18 HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOX and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied. Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 19 Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined. Protease Inhibitors: Concomitant administration of SPORANOX and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX and protease inhibitors must be given concomitantly. Other: • In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX may increase plasma concentrations of alfentanil. • Human pharmacokinetic data suggest that concomitant administration of SPORANOX and buspirone results in significant increases in plasma concentrations of buspirone. • SPORANOX may inhibit the metabolism of methylprednisolone. • In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and trimetrexate may inhibit the metabolism of trimetrexate. • SPORANOX enhances the anticoagulant effect of coumarin-like drugs, such as warfarin. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 20 itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOX therapy and for 2 months following the end of treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 21 Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX have not been established in pediatric patients. No pharmacokinetic data on SPORANOX Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. ADVERSE REACTIONS SPORANOX has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: General and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 22 in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 23 Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea 11 Vomiting 5 Diarrhea 3 Abdominal Pain 2 Anorexia 1 Body as a Whole Edema 4 Fatigue 3 Fever 3 Malaise 1 Skin and Appendages Rash 9 Pruritus 3 Central/Peripheral Nervous System Headache 4 Dizziness 2 Psychiatric Libido Decreased 1 Somnolence 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 *Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 24 Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 25 Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Post-marketing Experience Worldwide post-marketing experiences with the use of SPORANOX include adverse events of gastrointestinal origin, such as dyspepsia, nausea, vomiting, diarrhea, abdominal pain and constipation. Other reported adverse events include peripheral edema, congestive heart failure and pulmonary edema, headache, dizziness, peripheral neuropathy, menstrual disorders, reversible increases in hepatic enzymes, hepatitis, liver failure, hypokalemia, hypertriglyceridemia, alopecia, allergic reactions (such as pruritus, rash, urticaria, angioedema, anaphylaxis), Stevens-Johnson syndrome, and neutropenia. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information). OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX (itraconazole) Oral Solution or up to 3000 mg of SPORANOX (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 26 DOSAGE AND ADMINISTRATION SPORANOX (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX Capsules is a different preparation than SPORANOX Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously. • IV Injection: the recommended intravenous dose is 200 mg b.i.d. for four consecutive doses, followed by 200 mg once daily thereafter. Each intravenous dose should be infused over 1 hour. The safety and efficacy of SPORANOX Injection administered for greater than 14 days is not known. See complete prescribing information for SPORANOX (itraconazole) Injection. • Capsules: although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX Capsules and SPORANOX Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatotoxicity Labeling -062602 27 Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX. HOW SUPPLIED SPORANOX (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 x 10 capsules (NDC 50458-290-01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs x 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children.  Janssen 2001 7501618 U.S. Patent Nos. 4,267,179; 5,633,015 Revised June 2002 Distributed by: JANSSEN PHARMACEUTICA PRODUCTS, L.P. Titusville, New Jersey 08560, USA Capsule contents manufactured by: JANSSEN JANSSEN PHARMACEUTICA N.V. PHARMACEUTICA Beerse, Belgium PRODUCTS, L.P. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Patient Information 1 SPORANOX® 2 (itraconazole) Capsules 3 4 This summary contains important information about SPORANOX (SPOR-ah-nox). 5 This information is for patients who have been prescribed SPORANOX to treat fungal nail 6 infections. If your doctor prescribed SPORANOX for medical problems other than 7 fungal nail infections, ask your doctor if there is any information in this summary 8 that does not apply to you. Read this information carefully each time you start to use 9 SPORANOX. This information does not take the place of discussion between you and 10 your doctor. Only your doctor can decide if SPORANOX is the right treatment for you. 11 If you do not understand some of this information or have any questions, talk with your 12 doctor or pharmacist. 13 14 What Is The Most Important Information I Should Know About SPORANOX? 15 16 SPORANOX is used to treat fungal nail infections. However, SPORANOX is not for 17 everyone. Do not take SPORANOX for fungal nail infections if you have had heart 18 failure, including congestive heart failure. You should not take SPORANOX if you 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI are taking certain medicines that could lead to serious or life-threatening medical 20 problems. (See “Who Should Not Take SPORANOX?” below). 21 22 If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor 23 if it is safe for you to take SPORANOX. 24 25 What Happens If I Have A Fungal Nail Infection? 26 27 Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus 28 infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If 29 not treated, the fungus may spread under the nail towards the cuticle. If the fungus 30 spreads, more of the nail may change color, may become thick or brittle, and the tip of the 31 nail may become raised. In some patients, this can cause pain and discomfort. 32 33 What Is SPORANOX? 34 35 SPORANOX is a prescription medicine used to treat fungal infections of the toenails and 36 fingernails. It is also used to treat some types of fungal infections in other areas of your 37 body. We do not know if SPORANOX works in children with fungal nail infections or if 38 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI it is safe for children to take. 39 40 SPORANOX comes in the form of capsules and liquid (oral solution). The capsule and 41 liquid forms work differently, so you should not use one in place of the other. This Patient 42 Information discusses only the capsule form of SPORANOX. You will get these capsules 43 in a medicine bottle or a SPORANOX PulsePak®. The PulsePak contains 28 capsules for 44 treatment of your fungal nail infection. 45 46 SPORANOX goes into your bloodstream and travels to the source of the infection 47 underneath the nail so that it can fight the infection there. Improved nails may not be 48 obvious for several months after the treatment period is finished because it usually takes 49 about 6 months to grow a new fingernail and 12 months to grow a new toenail. 50 51 Who Should Not Take SPORANOX? 52 53 SPORANOX is not for everyone. Your doctor will decide if SPORANOX is the right 54 treatment for you. Some patients should not take SPORANOX because they may have 55 certain health problems or may be taking certain medicines that could lead to serious 56 or life-threatening medical problems. 57 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 58 Tell your doctor and pharmacist the name of all the prescription and non-prescription 59 medicines you are taking, including dietary supplements and herbal remedies. Also tell 60 your doctor about any other medical conditions you have had, especially heart, lung, liver 61 or kidney conditions. 62 63 Never take SPORANOX if you: 64 65 • have had heart failure, including congestive heart failure. 66 67 • are taking any of the medicines listed below. Dangerous or even life-threatening 68 abnormal heartbeats could result: 69 • quinidine (such as Cardioquin®, Quinaglute®, Quinidex®) 70 • dofetilide (such as Tikosyn) 71 • cisapride (such as Propulsid®) 72 • pimozide (such as Orap®) 73 74 • are taking any of the following medicines: 75 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI • lovastatin (such as Mevacor®, Advicor) 76 • simvastatin (such as Zocor®) 77 • triazolam (such as Halcion®) 78 • midazolam (such as Versed®) 79 80 • have ever had an allergic reaction to itraconazole or any of the other ingredients in 81 SPORANOX Capsules. Ask your doctor or pharmacist for a list of these 82 ingredients. 83 84 What Should I Know About SPORANOX and Pregnancy or Breast Feeding? 85 86 Never take SPORANOX if you have a fungal nail infection and are pregnant or planning 87 to become pregnant within 2 months after you have finished your treatment. 88 89 If you are able to become pregnant, you should use effective birth control during 90 SPORANOX treatment and for 2 months after finishing treatment. Ask your doctor about 91 effective types of birth control. 92 93 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI If you are breast-feeding, talk with your doctor about whether you should take Sporanox. 94 95 How Should I Take SPORANOX? 96 97 Always take SPORANOX Capsules during or right after a full meal. 98 99 Your doctor will decide the right dose for you. Depending on your infection, you will 100 take SPORANOX once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing 101 schedule. You will receive either a bottle of capsules or a PulsePak. Do not skip any 102 doses. Be sure to finish all your SPORANOX as prescribed by your doctor. 103 If you have ever had liver problems, your doctor should do a blood test to check your 104 105 condition. If you haven’t had liver problems, your doctor may recommend blood tests to 106 107 check the condition of your liver because patients taking SPORANOX can 108 109 develop liver problems. 110 111 If you forget to take or miss doses of SPORANOX, ask your doctor what you should do 112 with the missed doses. 113 114 The SPORANOX PulsePak 115 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 116 If you use the PulsePak, you will take SPORANOX for 1 week and then take no 117 SPORANOX for the next 3 weeks before repeating the 1-week treatment. This is called 118 “pulse dosing.” The SPORANOX PulsePak contains enough medicine for one “pulse” (1 119 week of treatment). 120 121 The SPORANOX PulsePak comes with special instructions. It contains 7 pouches—one 122 for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at 123 the back of the card, fold it back along the dashed line and peel away the backing so that 124 you can remove 2 capsules. 125 126 • Take 2 capsules in the morning and 2 capsules in the evening. This means you 127 will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all 128 of the capsules in the PulsePak box. 129 130 • After you finish the PulsePak, do not take any SPORANOX for the next 3 weeks. 131 Even though you are not taking any capsules during this time, SPORANOX keeps 132 working inside your nails to help fight the fungal infection. 133 134 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI • You will need more than one “pulse” to treat your fungal nail infection. When 135 your doctor prescribes another pulse treatment, be sure to get your refill before the 136 end of week 4. 137 138 139 140 141 142 SPORANOX Pulse Dosing Take 2 SPORANOX capsules twice a day for 1 week Day1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 AM PM AM PM AM PM AM PM AM PM AM PM AM PM Week 1 // // // // // // // // // // // // // // This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Week 2 Week 3 Week 4 For the next 3 weeks, do not take any SPORANOX capsules. Remember to get a refill before the end of Week 4 when your doctor prescribes another PulsePak. 143 What Are the Possible Side Effects of SPORANOX? 144 145 The most common side effects that cause people to stop treatment either for a short time 146 or completely include: skin rash, high triglyceride test results, high liver test results, and 147 digestive system problems (such as nausea, bloating, and diarrhea). 148 149 Stop SPORANOX and call your doctor right away if you develop shortness of breath; 150 have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually 151 tired; cough up white or pink phlegm; or have unusual fast heartbeats. In rare cases, 152 patients taking SPORANOX could develop serious heart problems, and these could be 153 warning signs of heart failure. 154 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 155 Stop SPORANOX and call your doctor right away if you become unusually tired; lose 156 your appetite; or develop nausea or vomiting, a yellow color to your skin or eyes, or dark 157 colored urine or pale stools (bowel movements). In rare cases, patients taking 158 SPORANOX could develop serious liver problems and these could be warning signs. 159 160 Call your doctor right away if you develop tingling or numbness in your extremities 161 (hands or feet). 162 These are not all the side effects of SPORANOX. Your doctor or pharmacist can give you 163 a more complete list. 164 165 What Should I Do If I Take An Overdose of SPORANOX? 166 167 If you think you took too much SPORANOX, call your doctor or local poison control 168 center, or go to the nearest hospital emergency room right away. 169 170 How Should I Store SPORANOX? 171 172 Keep all medicines, including SPORANOX, out of the reach of children. 173 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 174 Store SPORANOX Capsules and the PulsePak at room temperature in a dry place away 175 from light. 176 177 General Advice About SPORANOX 178 179 Medicines are sometimes prescribed for conditions that are not mentioned in patient 180 information leaflets. Do not use SPORANOX for a condition for which it was not 181 prescribed. Do not give SPORANOX to other people, even if they have the same 182 symptoms you have. It may harm them. 183 184 This leaflet summarizes the most important information about SPORANOX. If you would 185 like more information, talk with your doctor. You can ask your doctor or pharmacist for 186 information about SPORANOX that is written for health professionals. 187 188 You can also call 1-800-JANSSEN or visit the SPORANOX Internet site at 189 www.sporanox.com and the Janssen Internet site at www.us.janssen.com. 190 191 This patient information has been approved by the U.S. Food and Drug Administration. 192 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI 193 The following are registered trademarks of their respective manufacturers: 194 Mevacor® (Merck & Co., Inc.), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), 195 Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), 196 Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), 197 Propulsid® (Janssen Pharmaceutica Products, L.P.), and Orap® (Gate Pharmaceuticals) 198 199 Corporate Logo 200 © Janssen Pharmaceutica Products, L.P. 2002 201 Part Number 202 Printed in USA/ April, 2002. 203 204 205 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Renata Albrecht 7/17/02 12:42:21 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:41.767623	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20083s28s31lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 31}
12,191	SPORANOX PPI Janssen proposal March 26, 2002 Patient Information 1 March 26, 2002 2 SPORANOX® 3 (itraconazole) Capsules 4 strikeout=deleted 5 double underline=added 6 7 This summary contains important information about SPORANOX (SPOR-ah-nox). This 8 information is for patients who have been prescribed SPORANOX to treat fungal nail infections. 9 If your doctor prescribed SPORANOX for medical problems other than fungal nail 10 infections, ask your doctor if there is any information in this summary that does not 11 apply to you. Read this information carefully each time you start to use SPORANOX. This 12 information does not take the place of discussion between you and your doctor. Only your 13 doctor can decide if SPORANOX is the right treatment for you. If you do not understand some 14 of this information or have any questions, talk with your doctor or pharmacist. 15 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 What Is The Most Important Information I Should Know About SPORANOX? 17 18 SPORANOX is used to treat fungal nail infections. However, SPORANOX is not for 19 everyone. Do not take SPORANOX for fungal nail infections if you have had heart 20 failure, including congestive heart failure. You should not take SPORANOX if you are 21 taking certain medicines that could lead to serious or life-threatening medical problems. 22 (See “Who Should Not Take SPORANOX?” below). 23 24 If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is 25 safe for you to take SPORANOX. 26 27 What Happens If I Have A Fungal Nail Infection? 28 29 Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects 30 the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the 31 fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may 32 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 change color, may become thick or brittle, and the tip of the nail may become raised. In some 33 patients, this can cause pain and discomfort. 34 35 What Is SPORANOX? 36 37 SPORANOX is a prescription medicine used to treat fungal infections of the toenails and 38 fingernails. It is also used to treat some types of fungal infections in other areas of your body. 39 We do not know if SPORANOX works in children with fungal nail infections or if it is safe for 40 children to take. 41 42 SPORANOX comes in the form of capsules and liquid (oral solution). The capsule and liquid 43 forms work differently, so you should not use one in place of the other. This Patient Information 44 discusses only the capsule form of SPORANOX. You will get these capsules in a medicine 45 bottle or a SPORANOX PulsePak®. The PulsePak contains 28 capsules for treatment of your 46 fungal nail infection. 47 48 SPORANOX goes into your bloodstream and travels to the source of the infection underneath 49 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 the nail so that it can fight the infection there. Improved nails may not be obvious for several 50 months after the treatment period is finished because it usually takes about 6 months to grow a 51 new fingernail and 12 months to grow a new toenail. 52 53 Who Should Not Take SPORANOX? 54 55 SPORANOX is not for everyone. Your doctor will decide if SPORANOX is the right 56 treatment for you. Some patients should not take SPORANOX because they may have 57 certain health problems or may be taking certain medicines that could lead to serious or 58 life-threatening medical problems. 59 60 Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines 61 you are taking, including dietary supplements and herbal remedies. Also tell your doctor about 62 any other medical conditions you have had, especially heart, lung, liver or kidney conditions. 63 64 Never take SPORANOX if you: 65 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 66 • have had heart failure, including congestive heart failure. 67 68 • are taking any of the medicines listed below. Dangerous or even life-threatening 69 abnormal heartbeats could result: 70 • quinidine (such as Cardioquin®, Quinaglute®, Quinidex®) 71 • dofetilide (such as Tikosyn) 72 • cisapride (such as Propulsid®) 73 • pimozide (such as Orap®) 74 75 • are taking any of the following medicines: 76 • lovastatin (such as Mevacor®) 77 • simvastatin (such as Zocor®) 78 • triazolam (such as Halcion®) 79 • midazolam (such as Versed®) 80 81 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 • have ever had an allergic reaction to itraconazole or any of the other ingredients in 82 SPORANOX Capsules. Ask your doctor or pharmacist for a list of these ingredients. 83 84 What Should I Know About SPORANOX and Pregnancy or Breast Feeding? 85 86 Never take SPORANOX if you have a fungal nail infection and are pregnant or planning to 87 become pregnant within 2 months after you have finished your treatment. 88 89 If you are able to become pregnant, you should use effective birth control during SPORANOX 90 treatment and for 2 months after finishing treatment. Ask your doctor about effective types of 91 birth control. 92 93 If you are breast-feeding, talk with your doctor about whether you should take Sporanox. 94 95 How Should I Take SPORANOX? 96 97 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 Always take SPORANOX Capsules during or right after a full meal. 98 99 Your doctor will decide the right dose for you. Depending on your infection, you will take 100 SPORANOX once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing schedule. 101 You will receive either a bottle of capsules or a PulsePak. Do not skip any doses. Be sure to 102 finish all your SPORANOX as prescribed by your doctor. 103 If you have ever had liver problems, your doctor should do a blood test to check your 104 105 condition. If you haven’t had liver problems, your doctor may recommend blood tests to 106 107 check the condition of your liver because patients taking itraconazole SPORANOX can 108 109 develop liver problems. 110 111 If you forget to take or miss doses of SPORANOX, ask your doctor what you should do with 112 the missed doses. 113 114 The SPORANOX PulsePak 115 116 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 If you use the PulsePak, you will take SPORANOX for 1 week and then take no SPORANOX 117 for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The 118 SPORANOX PulsePak contains enough medicine for one “pulse” (1 week of treatment). 119 120 The SPORANOX PulsePak comes with special instructions. It contains 7 pouches—one for 121 each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of 122 the card, fold it back along the dashed line and peel away the backing so that you can remove 2 123 capsules. 124 125 • Take 2 capsules in the morning and 2 capsules in the evening. This means you will take 126 4 capsules a day for 7 days. At the end of 7 days, you will have taken all of the capsules 127 in the PulsePak box. 128 129 • After you finish the PulsePak, do not take any SPORANOX for the next 3 weeks. Even 130 though you are not taking any capsules during this time, SPORANOX keeps working 131 inside your nails to help fight the fungal infection. 132 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 133 • You will need more than one “pulse” to treat your fungal nail infection. When your 134 doctor prescribes another pulse treatment, be sure to get your refill before the end of 135 week 4. 136 137 138 139 140 141 SPORANOX Pulse Dosing Take 2 SPORANOX capsules twice a day for 1 week Day1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 AM PM AM PM AM PM AM PM AM PM AM PM AM PM Week 1 // // // // // // // // // // // // // // Week 2 For the next 3 weeks, do not take any SPORANOX capsules. Remember to get a refill before the end of Week 4 when your doctor prescribes another PulsePak. Week 3 Week 4 142 What Are the Possible Side Effects of SPORANOX? 143 144 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 The most common side effects that cause people to stop treatment either for a short time or 145 completely include: skin rash, high triglyceride test results, high liver test results, and digestive 146 system problems (such as nausea, bloating, and diarrhea). 147 148 Stop SPORANOX and call your doctor right away if you develop shortness of breath; have 149 unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up 150 white or pink phlegm; or have unusual fast heartbeats. In rare cases, patients taking 151 SPORANOX could develop serious heart problems, and these could be warning signs of heart 152 failure. 153 154 Stop SPORANOX and call your doctor right away if you become unusually tired; lose your 155 appetite; or develop nausea or vomiting, a yellow color to your skin or eyes, or dark colored 156 urine or pale stools (bowel movements). In rare cases, patients taking SPORANOX could 157 develop serious liver problems and these could be warning signs. 158 159 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 Call your doctor right away if you develop tingling or numbness in your extremities (hands or 160 feet). 161 These are not all the side effects of SPORANOX. Your doctor or pharmacist can give you a 162 more complete list. 163 164 What Should I Do If I Take An Overdose of SPORANOX? 165 166 If you think you took too much SPORANOX, call your doctor or local poison control center, or 167 go to the nearest hospital emergency room right away. 168 169 How Should I Store SPORANOX? 170 171 Keep all medicines, including SPORANOX, out of the reach of children. 172 173 Store SPORANOX Capsules and the PulsePak at room temperature in a dry place away from 174 light. 175 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 176 General Advice About SPORANOX 177 178 Medicines are sometimes prescribed for conditions that are not mentioned in patient information 179 leaflets. Do not use SPORANOX for a condition for which it was not prescribed. Do not give 180 SPORANOX to other people, even if they have the same symptoms you have. It may harm 181 them. 182 183 This leaflet summarizes the most important information about SPORANOX. If you would like 184 more information, talk with your doctor. You can ask your doctor or pharmacist for information 185 about SPORANOX that is written for health professionals. 186 187 You can also call 1-800-JANSSEN or visit the SPORANOX Internet site at 188 www.sporanox.com and the Janssen Internet site at www.us.janssen.com. 189 190 This patient information has been approved by the U.S. Food and Drug Administration. 191 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX PPI Janssen proposal March 26, 2002 192 The following are registered trademarks of their respective manufacturers: 193 Mevacor® (Merck & Co., Inc.), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® 194 (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex 195 Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid® (Janssen 196 Pharmaceutica Products, L.P.), and Orap® (Gate Pharmaceuticals) 197 198 Corporate Logo 199 © Janssen Pharmaceutica Products, L.P. 2002 200 Part Number 201 Printed in USA/ April, 2002. 202 203 204 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Renata Albrecht 4/11/02 12:05:36 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:41.789778	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20083s29lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 29}
12,193	CBE-January 2004 1 JANSSEN PHARMACEUTICA PRODUCTS, L.P. SPORANOX (ITRACONAZOLE) CAPSULES Congestive Heart Failure SPORANOX (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) Drug Interactions: Coadministration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) with SPORANOX® (itraconazole) Capsules, Injection or Oral Solution is contraindicated. SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information. DESCRIPTION SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 2 (insert structure) (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5- one mixture with (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2S,4R)-2-(2,4-dichlorophenyl)-2- (1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2- 1,2,4-triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5- one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n- octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are gelatin, hydroxypropyl methylcellulose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.) The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 3 The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below: 50 mg (fed) 100 mg (fed) 100 mg (fasted) 200 mg (fed) Cmax (ng/mL) 45 ± 16* 132 ± 67 38 ± 20 289 ± 100 Tmax (hours) 3.2 ± 1.3 4.0 ± 1.1 3.3 ± 1.0 4.7 ± 1.4 AUC0-∞ (ng·h/mL) 567 ± 264 1899 ± 838 722 ± 289 5211 ± 2116 mean + standard deviation Doubling the SPORANOX® dose results in approximately a three-fold increase in the itraconazole plasma concentrations. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX® Capsules with or without a full meal: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 4 Itraconazole Hydroxyitraconazole Fed Fasted Fed Fasted Cmax (ng/mL) 239 ± 85 140 ± 65 397 ± 103 286 ± 101 Tmax (hours) 4.5 ± 1.1 3.9 ± 1.0 5.1 ± 1.6 4.5 ± 1.1 AUC0-∞ (ng·h/mL) 3423 ± 1154 2094 ± 905 7978 ± 2648 5191 ± 2489 t1/2 (hours) 21 ± 5 21 ± 7 12 ± 3 12 ± 3 mean ± standard deviation Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX® Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX® Capsules were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX® Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX® Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When SPORANOX® Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 5 Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX® Capsules b.i.d.(with a full meal) for 15 days: Itraconazole Hydroxyitraconazole Cmax (ng/mL) 2282 ± 514 3488 ± 742 Cmin (ng/mL) 1855 ± 535 3349 ± 761 Tmax (hours) 4.6 ± 1.8 3.4 ± 3.4 AUC0-12 h (ng·h/mL) 22569 ± 5375 38572 ± 8450 t1/2 (hours) 64 ± 32 56 ± 24 mean ± standard deviation The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 6 Special Populations: Renal Insufficiency: A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. x 1.73 m2, the bioavailability was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Hepatic Insufficiency: A pharmacokinetic study using a single 100-mg dose of itraconazole (one 100-mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX Capsules, SPORANOX should be discontinued. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post- marketing Experience for more information.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 7 MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum and Blastomyces dermatitidis. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species. Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 8 less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 9 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non- concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non- concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 10 Aspergillosis: Analyses were conducted on data from an open-label, “single-patient- use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail: Analyses were conducted on data from three double- blind, placebo-controlled studies (N=214 total; 110 given SPORANOX Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX Capsules b.i.d., followed by a 3-week period without SPORANOX, which was followed by a second 1-week pulse of 200 mg of SPORANOX Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 11 Congestive Heart Failure: SPORANOX (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Post-marketing Experience.) Drug Interactions: Concomitant administration of SPORANOX (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with SPORANOX. HMG CoA- reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with SPORANOX. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOX should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX to patients with hypersensitivity to other azoles. WARNINGS SPORANOX (itraconazole) Capsules and SPORANOX Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Hepatic Effects: SPORANOX has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 12 these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX use or reinstitution of treatment with SPORANOX is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: SPORANOX Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX Capsules, discontinue administration. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 13 fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS General: Rare cases of serious hepatotoxicity have been observed with Sporanox treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Sporanox. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. If neuropathy occurs that may be attributable to Sporanox capsules, the treatment should be discontinued. SPORANOX (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Information for Patients: • The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 14 interchangeably with SPORANOX® Oral Solution. • Instruct patients to take SPORANOX Capsules with a full meal. • Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX administration, they should discontinue SPORANOX and contact their healthcare provider immediately. • Instruct patients to stop Sporanox treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. • Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1 below and the following drug class subheadings that follow): 1. SPORANOX may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 15 2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX may not be effective in patients concomitantly taking SPORANOX and one of these drugs. Therefore, administration of these drugs with SPORANOX is not recommended. 3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 16 Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by SPORANOX1 Drug plasma concentration increased by itraconazole Antiarrhythmics digoxin, dofetilide2, quinidine2, disopyramide Anticonvulsants carbamazepine Antimycobacterials rifabutin Antineoplastics busulfan, docetaxel, vinca alkaloids Antipsychotics pimozide2 Benzodiazepines alprazolam, diazepam, midazolam,2,3 triazolam2 Calcium Channel Blockers dihydropyridines, verapamil Gastrointestinal Motility Agents cisapride2 HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2 Immunosuppressants cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics oral hypoglycemics Protease Inhibitors indinavir, ritonavir, saquinavir Other levacetylmethadol (levomethadyl), ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, trimetrexate, warfarin, cilostazol, eletriptan Decrease plasma concentration of itraconazole Anticonvulsants carbamazepine, phenobarbital, phenytoin Antimycobacterials isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors Non-nucleoside Reverse Transcriptase Inhibitors nevirapine Increase plasma concentration of itraconazole Macrolide Antibiotics clarithromycin, erythromycin Protease Inhibitors indinavir, ritonavir 1This list is not all-inclusive. 2Contraindicated with SPORANOX based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) 3For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 17 dofetilide with SPORANOX may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX and disopyramide are administered concomitantly. Concomitant administration of digoxin and SPORANOX has led to increased plasma concentrations of digoxin. Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and carbamazepine may inhibit the metabolism of carbamazepine. Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOX may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 18 Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Benzodiazepines: Concomitant administration of SPORANOX and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged. Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX Capsules. In a clinical study, when SPORANOX Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 19 Gastrointestinal Motility Agents: Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOX and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX Capsules 100 mg twice daily and the nucleoside reverse transcriptase This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 20 inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied. Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered. Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined. Protease Inhibitors: Concomitant administration of SPORANOX and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX and protease inhibitors must be given concomitantly. Other: • Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with SPORANOX could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and levacetylmethadol is contraindicated. • Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with SPORANOX is contraindicated. • Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when SPORANOX and halofantrine are administered concomitantly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 21 • In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX may increase plasma concentrations of alfentanil. • Human pharmacokinetic data suggest that concomitant administration of SPORANOX and buspirone results in significant increases in plasma concentrations of buspirone. • SPORANOX may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone and methylprednisolone. • In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and trimetrexate may inhibit the metabolism of trimetrexate. • SPORANOX enhances the anticoagulant effect of coumarin-like drugs, such as warfarin. • Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with SPORANOX. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 22 tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOX therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-marketing Experience.) Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 23 avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX have not been established in pediatric patients. No pharmacokinetic data on SPORANOX Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. ADVERSE REACTIONS SPORANOX has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: General and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 24 Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea 11 Vomiting 5 Diarrhea 3 Abdominal Pain 2 Anorexia 1 Body as a Whole Edema 4 Fatigue 3 Fever 3 Malaise 1 Skin and Appendages Rash 9 Pruritus 3 Central/Peripheral Nervous System Headache 4 Dizziness 2 Psychiatric Libido Decreased 1 Somnolence 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 *Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 25 Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 26 Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Post-marketing Experience Worldwide post-marketing experiences with the use of SPORANOX include adverse events of gastrointestinal origin, such as dyspepsia, nausea, vomiting, diarrhea, abdominal pain and constipation. Other reported adverse events include peripheral edema, congestive heart failure and pulmonary edema, headache, dizziness, peripheral neuropathy, menstrual disorders, reversible increases in hepatic enzymes, hepatitis, liver failure, hypokalemia, hypertriglyceridemia, alopecia, allergic reactions (such as pruritus, rash, urticaria, angioedema, anaphylaxis), Stevens-Johnson syndrome, anaphylactic, anaphylactoid and allergic reactions, photosensitivity and neutropenia. There is limited information on the use of SPORANOX during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information). OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 27 Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX (itraconazole) Oral Solution or up to 3000 mg of SPORANOX (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses. DOSAGE AND ADMINISTRATION SPORANOX (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX Capsules is a different preparation than SPORANOX Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously. • IV Injection: the recommended intravenous dose is 200 mg b.i.d. for four consecutive doses, followed by 200 mg once daily thereafter. Each intravenous dose should be infused over 1 hour. The safety and efficacy of SPORANOX Injection administered for greater than 14 days is not known. See complete prescribing information for SPORANOX (itraconazole) Injection. • Capsules: although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 28 SPORANOX Capsules and SPORANOX Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX. HOW SUPPLIED SPORANOX (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 x 10 capsules (NDC 50458-290-01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs x 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children.  Janssen 2001 7501621 U.S. Patent Nos. 4,267,179; 5,633,015 Revised January 2004 Distributed by: JANSSEN PHARMACEUTICA PRODUCTS, L.P. Titusville, New Jersey 08560, USA Capsule contents manufactured by: JANSSEN JANSSEN PHARMACEUTICA N.V. PHARMACEUTICA Beerse, Belgium PRODUCTS, L.P. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 1 SPORANOX PPI Patient Information 1 Janssen 100 mg 2 SPORANOX® 3 (itraconazole) Capsules 4 5 This summary contains important information about SPORANOX (SPOR-ah-nox). 6 This information is for patients who have been prescribed SPORANOX to treat fungal 7 nail infections. If your doctor prescribed SPORANOX for medical problems other 8 than fungal nail infections, ask your doctor if there is any information in this 9 summary that does not apply to you. Read this information carefully each time you 10 start to use SPORANOX. This information does not take the place of discussion 11 between you and your doctor. Only your doctor can decide if SPORANOX is the right 12 treatment for you. If you do not understand some of this information or have any 13 questions, talk with your doctor or pharmacist. 14 15 What Is the Most Important Information I Should Know About 16 SPORANOX? 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 2 SPORANOX PPI SPORANOX is used to treat fungal nail infections. However, SPORANOX is not for 18 everyone. Do not take SPORANOX for fungal nail infections if you have had heart 19 failure, including congestive heart failure. You should not take SPORANOX if you 20 are taking certain medicines that could lead to serious or life-threatening medical 21 problems. (See “Who Should Not Take SPORANOX?” below.) 22 23 If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor 24 if it is safe for you to take SPORANOX. 25 26 What Happens if I Have a Fungal Nail Infection? 27 28 Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus 29 infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If 30 not treated, the fungus may spread under the nail towards the cuticle. If the fungus 31 spreads, more of the nail may change color, may become thick or brittle, and the tip of the 32 nail may become raised. In some patients, this can cause pain and discomfort. 33 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 3 SPORANOX PPI What Is SPORANOX? 35 36 SPORANOX is a prescription medicine used to treat fungal infections of the toenails and 37 fingernails. It is also used to treat some types of fungal infections in other areas of your 38 body. We do not know if SPORANOX works in children with fungal nail infections or if 39 it is safe for children to take. 40 41 SPORANOX comes in the form of capsules and liquid (oral solution). The capsule and 42 liquid forms work differently, so you should not use one in place of the other. This Patient 43 Information discusses only the capsule form of SPORANOX. You will get these 44 capsules in a medicine bottle or a SPORANOX PulsePak®. The PulsePak contains 28 45 capsules for treatment of your fungal nail infection. 46 47 SPORANOX goes into your bloodstream and travels to the source of the infection 48 underneath the nail so that it can fight the infection there. Improved nails may not be 49 obvious for several months after the treatment period is finished because it usually takes 50 about 6 months to grow a new fingernail and 12 months to grow a new toenail. 51 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 4 SPORANOX PPI 52 Who Should Not Take SPORANOX? 53 54 SPORANOX is not for everyone. Your doctor will decide if SPORANOX is the right 55 treatment for you. Some patients should not take SPORANOX because they may 56 have certain health problems or may be taking certain medicines that could lead to 57 serious or life-threatening medical problems. 58 59 Tell your doctor and pharmacist the name of all the prescription and non-prescription 60 medicines you are taking, including dietary supplements and herbal remedies. Also tell 61 your doctor about any other medical conditions you have had, especially heart, lung, liver 62 or kidney conditions. 63 64 Never take SPORANOX if you: 65 66 • have had heart failure, including congestive heart failure. 67 68 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 5 SPORANOX PPI • are taking any of the medicines listed below. Dangerous or even life-threatening 69 abnormal heartbeats could result: 70 • quinidine (such as Cardioquin®, Quinaglute®, Quinidex®) 71 • dofetilide (such as Tikosyn) 72 • cisapride (such as Propulsid®) 73 • pimozide (such as Orap®) 74 • levacetylmethadol (such as Orlaam®) 75 76 • are taking any of the following medicines: 77 • lovastatin (such as Mevacor®, Advicor®, Altocor) 78 • simvastatin (such as Zocor®) 79 • triazolam (such as Halcion®) 80 • midazolam (such as Versed®) 81 • ergot alkaloids (such as Migranal®, Ergonovine, Cafergot®, 82 Methergine®) 83 84 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 6 SPORANOX PPI • have ever had an allergic reaction to itraconazole or any of the other ingredients in 85 SPORANOX Capsules. Ask your doctor or pharmacist for a list of these 86 ingredients. 87 88 What Should I Know About SPORANOX and Pregnancy or Breast Feeding? 89 90 Never take SPORANOX if you have a fungal nail infection and are pregnant or planning 91 to become pregnant within 2 months after you have finished your treatment. 92 93 If you are able to become pregnant, you should use effective birth control during 94 SPORANOX treatment and for 2 months after finishing treatment. Ask your doctor 95 about effective types of birth control. 96 97 If you are breast-feeding, talk with your doctor about whether you should take Sporanox. 98 99 How Should I Take SPORANOX? 100 101 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 7 SPORANOX PPI Always take SPORANOX Capsules during or right after a full meal. 102 103 Your doctor will decide the right dose for you. Depending on your infection, you will 104 take SPORANOX once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing 105 schedule. You will receive either a bottle of capsules or a PulsePak. Do not skip any 106 doses. Be sure to finish all your SPORANOX as prescribed by your doctor. 107 If you have ever had liver problems, your doctor should do a blood test to check your 108 109 condition. If you haven’t had liver problems, your doctor may recommend blood tests to 110 111 check the condition of your liver because patients taking SPORANOX can 112 113 develop liver problems. 114 115 If you forget to take or miss doses of SPORANOX, ask your doctor what you should do 116 with the missed doses. 117 118 The SPORANOX PulsePak 119 If you use the PulsePak, you will take SPORANOX for 1 week and then take no 120 SPORANOX for the next 3 weeks before repeating the 1-week treatment. This is called 121 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 8 SPORANOX PPI “pulse dosing.” The SPORANOX PulsePak contains enough medicine for one “pulse” 122 (1 week of treatment). 123 124 The SPORANOX PulsePak comes with special instructions. It contains 7 pouches- 125 one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking 126 at the back of the card, fold it back along the dashed line and peel away the backing so 127 that you can remove 2 capsules. 128 129 • Take 2 capsules in the morning and 2 capsules in the evening. This means you 130 will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all 131 of the capsules in the PulsePak box. 132 133 • After you finish the PulsePak, do not take any SPORANOX for the next 3 134 weeks. Even though you are not taking any capsules during this time, 135 SPORANOX keeps working inside your nails to help fight the fungal infection. 136 137 • You will need more than one “pulse” to treat your fungal nail infection. When 138 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 9 SPORANOX PPI your doctor prescribes another pulse treatment, be sure to get your refill before the 139 end of week 4. 140 141 142 143 144 145 SPORANOX Pulse Dosing Take 2 SPORANOX capsules twice a day for 1 week Day1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 AM PM AM PM AM PM AM PM AM PM AM PM AM PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 10 SPORANOX PPI Week 1 // // // // // // // // // // // // // // Week 2 Week 3 Week 4 For the next 3 weeks, do not take any SPORANOX capsules. Remember to get a refill before the end of Week 4 when your doctor prescribes another PulsePak. 146 What Are the Possible Side Effects of SPORANOX? 147 148 The most common side effects that cause people to stop treatment either for a short time 149 or completely include: skin rash, high triglyceride test results, high liver test results, and 150 digestive system problems (such as nausea, bloating, and diarrhea). 151 152 Stop SPORANOX and call your doctor right away if you develop shortness of breath; 153 have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually 154 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 11 SPORANOX PPI tired; cough up white or pink phlegm; or have unusual fast heartbeats. In rare cases, 155 patients taking SPORANOX could develop serious heart problems, and these could be 156 warning signs of heart failure. 157 158 Stop SPORANOX and call your doctor right away if you become unusually tired; 159 lose your appetite; or develop nausea or vomiting, a yellow color to your skin or eyes, or 160 dark colored urine or pale stools (bowel movements). In rare cases, patients taking 161 SPORANOX could develop serious liver problems and these could be warning signs. 162 163 Call your doctor right away if you develop tingling or numbness in your extremities 164 (hands or feet). 165 These are not all the side effects of SPORANOX. Your doctor or pharmacist can give 166 you a more complete list. 167 168 What Should I Do if I Take an Overdose of SPORANOX? 169 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 12 SPORANOX PPI If you think you took too much SPORANOX, call your doctor or local poison control 171 center, or go to the nearest hospital emergency room right away. 172 173 How Should I Store SPORANOX? 174 175 Keep all medicines, including SPORANOX, out of the reach of children. 176 177 Store SPORANOX Capsules and the PulsePak at room temperature in a dry place away 178 from light. 179 180 General Advice About SPORANOX 181 182 Medicines are sometimes prescribed for conditions that are not mentioned in patient 183 information leaflets. Do not use SPORANOX for a condition for which it was not 184 prescribed. Do not give SPORANOX to other people, even if they have the same 185 symptoms you have. It may harm them. 186 187 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 13 SPORANOX PPI This leaflet summarizes the most important information about SPORANOX. If you 188 would like more information, talk with your doctor. You can ask your doctor or 189 pharmacist for information about SPORANOX that is written for health professionals. 190 191 You can also call 1-800-JANSSEN or visit the SPORANOX Internet site at 192 www.sporanox.com and the Janssen Internet site at www.us.janssen.com. 193 194 This patient information has been approved by the U.S. Food and Drug Administration. 195 196 The following are registered trademarks of their respective manufacturers: 197 Mevacor® (Merck & Co., Inc.), Advicor® (Kos Pharmaceuticals, Inc.), Altocor (Andrx 198 Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche 199 Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex 200 Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid® (Janssen 201 Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel 202 Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis 203 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CBE-January 2004 14 SPORANOX PPI Pharmaceuticals Corporation), Methergine® (Novartis Pharmaceuticals Corporation) and 204 Orap® (Gate Pharmaceuticals) 205 206 Corporate Logo 207 © Janssen Pharmaceutica Products, L.P. 2002 208 7518702 209 Printed in USA/ Revised January 2004. 210 211 212 213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:41.951797	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20083s034,035lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 35}
12,194	SPORANOX® (itraconazole) Capsules Congestive Heart Failure: SPORANOX® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX® Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) Drug Interactions: Coadministration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) with SPORANOX® (itraconazole) Capsules, Injection or Oral Solution is contraindicated. SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine, concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information. DESCRIPTION SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chemical Structure (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4 triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2 1,2,4-triazolin-5-one mixture with (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2S,4R)-2 (2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4 yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4 triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2 1,2,4-triazolin-5-one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.) The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below: 50 mg (fed) 100 mg (fed) 100 mg (fasted) 200 mg (fed) Cmax (ng/mL) 45 ± 16* 132 ± 67 38 ± 20 289 ± 100 Tmax (hours) 3.2 ± 1.3 4.0 ± 1.1 3.3 ± 1.0 4.7 ± 1.4 AUC0-∞ (ng·h/mL) 567 ± 264 1899 ± 838 722 ± 289 5211 ± 2116 ∗ mean + standard deviation Doubling the SPORANOX® dose results in approximately a three-fold increase in the itraconazole plasma concentrations. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX® Capsules with or without a full meal: Itraconazole Hydroxyitraconazole Fed Fasted Fed Fasted Cmax (ng/mL) 239 ± 85* 140 ± 65 397 ± 103 286 ± 101 Tmax (hours) 4.5 ± 1.1 3.9 ± 1.0 5.1 ± 1.6 4.5 ± 1.1 AUC0-∞ (ng·h/mL) 3423 ± 1154 2094 ± 905 7978 ± 2648 5191 ± 2489 t1/2 (hours) 21 ± 5 21 ± 7 12 ± 3 12 ± 3 ∗mean ± standard deviation Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX® Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX® Capsules 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX® Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX® Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When SPORANOX® Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX® Capsules b.i.d.(with a full meal) for 15 days: Itraconazole Hydroxyitraconazole Cmax (ng/mL) 2282 ± 514* 3488 ± 742 Cmin (ng/mL) 1855 ± 535 3349 ± 761 Tmax (hours) 4.6 ± 1.8 3.4 ± 3.4 AUC0-12 h (ng·h/mL) 22569 ± 5375 38572 ± 8450 t1/2 (hours) 64 ± 32 56 ± 24 ∗mean ± standard deviation The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.) 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Populations: Renal Insufficiency: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. x 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Caution should be exercised when the drug is administered in this patient population. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Hepatic Insufficiency: Itraconazole is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. A pharmacokinetic study using a single oral 100 mg capsule dose of itraconazole was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of itraconazole. (See BOX WARNING, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX® Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX® Capsules, SPORANOX® should be discontinued. (See CONTRAINDICATIONS, WARNINGS, 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum, Blastomyces dermatitidis, Zygomycete, Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species. Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail: Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX® Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX® Capsules b.i.d., followed by a 3-week period without SPORANOX® , which was followed by a second 1-week pulse of 200 mg of SPORANOX® Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS Congestive Heart Failure: SPORANOX® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Post-marketing Experience.) Drug Interactions: Concomitant administration of SPORANOX® (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with SPORANOX®. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX®. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with SPORANOX®. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX® to patients with hypersensitivity to other azoles. WARNINGS SPORANOX® (itraconazole) Capsules and SPORANOX® Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatic Effects: SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX® use or reinstitution of treatment with SPORANOX® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: SPORANOX® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX® therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX® Capsules, discontinue administration. Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX® Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. SPORANOX® has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS General: SPORANOX® (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with Sporanox® treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox® is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Sporanox®. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Neuropathy: If neuropathy occurs that may be attributable to Sporanox® capsules, the treatment should be discontinued. Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions; CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Information for Patients: • The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used interchangeably with SPORANOX® Oral Solution. • Instruct patients to take SPORANOX® Capsules with a full meal. • Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX® administration, they should discontinue SPORANOX® and contact their healthcare provider immediately. • Instruct patients to stop Sporanox® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. • Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. • Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (see Table 1 below and the following drug class subheadings that follow): 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1. SPORANOX® may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX®. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX® therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. 2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX® may not be effective in patients concomitantly taking SPORANOX® and one of these drugs. Therefore, administration of these drugs with SPORANOX® is not recommended. 3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX® . 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by SPORANOX®1 Drug plasma concentration increased by itraconazole Antiarrhythmics digoxin, dofetilide, 2 quinidine, 2 disopyramide Anticonvulsants carbamazepine Antimycobacterials rifabutin Antineoplastics busulfan, docetaxel, vinca alkaloids Antipsychotics pimozide2 Benzodiazepines alprazolam, diazepam, midazolam,2,3 triazolam2 Calcium Channel Blockers dihydropyridines (including nisoldipine2), verapamil Gastrointestinal Motility Agents cisapride2 HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2 Immunosuppressants cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics oral hypoglycemics Protease Inhibitors indinavir, ritonavir, saquinavir Other levacetylmethadol (levomethadyl),2 ergot alkaloids,2 halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl Decrease plasma concentration of itraconazole Anticonvulsants carbamazepine, phenobarbital, phenytoin Antimycobacterials isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors Non-nucleoside Reverse Transcriptase Inhibitors nevirapine Increase plasma concentration of itraconazole Macrolide Antibiotics clarithromycin, erythromycin Protease Inhibitors indinavir, ritonavir 1 This list is not all-inclusive. 2 Contraindicated with SPORANOX® based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) 3 For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX® may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and disopyramide are administered concomitantly. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concomitant administration of digoxin and SPORANOX® has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein. Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX® was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX® and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine. Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX® could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOX® may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Benzodiazepines: Concomitant administration of SPORANOX® and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX® and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged. Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX® and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction, therefore the concomitant administration of SPORANOX® and nisoldipine is contraindicated. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX® Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX® should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX® Capsules. In a clinical study, when SPORANOX® Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. Gastrointestinal Motility Agents: Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX® inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX® with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOX® and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX® Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied. Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered. 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined. Protease Inhibitors: Concomitant administration of SPORANOX® and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX® and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX® and protease inhibitors must be given concomitantly. Other: • Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and levacetylmethadol is contraindicated. • Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with SPORANOX® is contraindicated. • Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and halofantrine are administered concomitantly. • In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX® may increase plasma concentrations of alfentanil. • Human pharmacokinetic data suggest that concomitant administration of SPORANOX® and buspirone results in significant increases in plasma concentrations of buspirone. • SPORANOX® may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone. • In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and trimetrexate may inhibit the metabolism of trimetrexate. 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • SPORANOX® enhances the anticoagulant effect of coumarin-like drugs, such as warfarin. • Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with SPORANOX® . • Fentanyl plasma concentrations could be increased or prolonged by concomitant use of SPORANOX® and may cause potentially fatal respiratory depression. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are no studies in pregnant women. SPORANOX® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOX® therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-marketing Experience.) Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX® have not been established in pediatric patients. No pharmacokinetic data on SPORANOX® Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX® Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use: Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). Itraconazole should be used with care in elderly patients (see PRECAUTIONS). HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX® use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: General and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea 11 Vomiting 5 Diarrhea 3 Abdominal Pain 2 Anorexia 1 Body as a Whole Edema 4 Fatigue 3 Fever 3 Malaise 1 Skin and Appendages Rash* 9 Pruritus 3 Central/Peripheral Nervous System Headache 4 Dizziness 2 Psychiatric Libido Decreased 1 Somnolence 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 ∗ Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Post-marketing Experience Adverse drug reactions that have been identified during post-approval use of SPORANOX® (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda frequency or establishing a causal relationship to drug exposure is not always possible. Postmarketing Reports of Adverse Drug Reactions Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia Immune system disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Metabolism and nutrition disorders: Hypertriglyceridemia, hypokalemia Nervous system disorders: Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness Eye disorders: Visual disturbances, including vision blurred and diplopia Ear and labyrinth disorders: Transient or permanent hearing loss, tinnitus Cardiac disorders: Congestive heart failure Respiratory, thoracic and mediastinal Pulmonary edema disorders: Gastrointestinal disorders: Abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia Hepato-biliary disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, pruritus Musculoskeletal and connective tissue Myalgia, arthralgia disorders: Renal and urinary disorders: Urinary incontinence, pollakiuria Reproductive system and breast Menstrual disorders, erectile dysfunction disorders: General disorders and administration site Peripheral edema conditions: There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX® has not been established. (See CLINICAL 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.) OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX® (itraconazole) Oral Solution or up to 3000 mg of SPORANOX® (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses. DOSAGE AND ADMINISTRATION SPORANOX® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX® Capsules is a different preparation than SPORANOX® Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously. • IV Injection: the recommended intravenous dose is 200 mg b.i.d. for four consecutive doses, followed by 200 mg once daily thereafter. Each intravenous dose should be infused over 1 hour. The safety and efficacy of SPORANOX® Injection administered for greater than 14 days is not known. See complete prescribing information for SPORANOX® (itraconazole) Injection. • Capsules: although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX® Capsules and SPORANOX® Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX® . Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS for further information.) Use in Patients with Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.) HOW SUPPLIED SPORANOX® (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 x 10 capsules (NDC 50458-290-01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs x 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children. 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda © Janssen 2001 U.S. Patent Nos. 4,267,179; 5,633,015 TBD Revised TBD Capsule contents manufactured by: Janssen Pharmaceutica N.V. Olen, Belgium Manufactured by: JOLLC, Gurabo, Puerto Rico 00778 Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION 100 mg SPORANOX® (itraconazole) Capsules This summary contains important information about SPORANOX® (SPOR-ah-nox). This information is for patients who have been prescribed SPORANOX® to treat fungal nail infections. If your doctor prescribed SPORANOX® for medical problems other than fungal nail infections, ask your doctor if there is any information in this summary that does not apply to you. Read this information carefully each time you start to use SPORANOX®. This information does not take the place of discussion between you and your doctor. Only your doctor can decide if SPORANOX® is the right treatment for you. If you do not understand some of this information or have any questions, talk with your doctor or pharmacist. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT SPORANOX®? SPORANOX® is used to treat fungal nail infections. However, SPORANOX® is not for everyone. Do not take SPORANOX® for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take SPORANOX® if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See “Who Should Not Take SPORANOX®?” below.) If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is safe for you to take SPORANOX® . WHAT HAPPENS IF I HAVE A FUNGAL NAIL INFECTION? Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHAT IS SPORANOX® ? SPORANOX® is a prescription medicine used to treat fungal infections of the toenails and fingernails. It is also used to treat some types of fungal infections in other areas of your body. We do not know if SPORANOX® works in children with fungal nail infections or if it is safe for children to take. SPORANOX® comes in the form of capsules and liquid (oral solution). The capsule and liquid forms work differently, so you should not use one in place of the other. This Patient Information discusses only the capsule form of SPORANOX®. You will get these capsules in a medicine bottle or a SPORANOX PulsePak®. The PulsePak® contains 28 capsules for treatment of your fungal nail infection. SPORANOX® goes into your bloodstream and travels to the source of the infection underneath the nail so that it can fight the infection there. Improved nails may not be obvious for several months after the treatment period is finished because it usually takes about 6 months to grow a new fingernail and 12 months to grow a new toenail. WHO SHOULD NOT TAKE SPORANOX®? SPORANOX® is not for everyone. Your doctor will decide if SPORANOX® is the right treatment for you. Some patients should not take SPORANOX® because they may have certain health problems or may be taking certain medicines that could lead to serious or life-threatening medical problems. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking, including dietary supplements and herbal remedies. Also tell your doctor about any other medical conditions you have had, especially heart, lung, liver or kidney conditions. Never take SPORANOX® if you: • have had heart failure, including congestive heart failure. • are taking any of the medicines listed below. Dangerous or even life-threatening abnormal heartbeats could result: • quinidine (such as Cardioquin®, Quinaglute®, Quinidex®) • dofetilide (such as Tikosyn™) • cisapride (such as Propulsid®) • pimozide (such as Orap®) • levacetylmethadol (such as Orlaam®) 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • are taking any of the following medicines: • lovastatin (such as Mevacor®, Advicor®, Altocor™) • simvastatin (such as Zocor®) • triazolam (such as Halcion®) • midazolam (such as Versed®) • nisoldipine (such as Sular®) • ergot alkaloids (such as Migranal®, Ergonovine, Cafergot®, Methergine®) • have ever had an allergic reaction to itraconazole or any of the other ingredients in SPORANOX® Capsules. Ask your doctor or pharmacist for a list of these ingredients. Taking SPORANOX® with certain other medicines could lead to serious or life-threatening medical problems. For example, taking fentanyl, a strong opioid narcotic pain medicine, with SPORANOX® could cause serious side effects, including trouble breathing, that may be life-threatening. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking. Your doctor will decide if SPORANOX® is the right treatment for you. WHAT SHOULD I KNOW ABOUT SPORANOX® AND PREGNANCY OR BREAST FEEDING? Never take SPORANOX® if you have a fungal nail infection and are pregnant or planning to become pregnant within 2 months after you have finished your treatment. If you are able to become pregnant, you should use effective birth control during SPORANOX® treatment and for 2 months after finishing treatment. Ask your doctor about effective types of birth control. If you are breast-feeding, talk with your doctor about whether you should take SPORANOX® . HOW SHOULD I TAKE SPORANOX® ? Always take SPORANOX® Capsules during or right after a full meal. Your doctor will decide the right dose for you. Depending on your infection, you will take SPORANOX® once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing schedule. You will receive either a bottle of capsules or a PulsePak®. Do not skip any doses. Be sure to finish all your SPORANOX® as prescribed by your doctor. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven’t had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking SPORANOX® can develop liver problems. If you forget to take or miss doses of SPORANOX®, ask your doctor what you should do with the missed doses. THE SPORANOX PulsePak® If you use the PulsePak®, you will take SPORANOX® for 1 week and then take no SPORANOX® for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The SPORANOX PulsePak® contains enough medicine for one “pulse” (1 week of treatment). The SPORANOX PulsePak® comes with special instructions. It contains 7 pouches-one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of the card, fold it back along the dashed line and peel away the backing so that you can remove 2 capsules. • Take 2 capsules in the morning and 2 capsules in the evening. This means you will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all of the capsules in the PulsePak® box. • After you finish the PulsePak®, do not take any SPORANOX® for the next 3 weeks. Even though you are not taking any capsules during this time, SPORANOX® keeps working inside your nails to help fight the fungal infection. • You will need more than one “pulse” to treat your fungal nail infection. When your doctor prescribes another pulse treatment, be sure to get your refill before the end of week 4. SPORANOX® Pulse Dosing Take 2 SPORANOX® capsules twice a day for 1 week Day1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 AM PM AM PM AM PM AM PM AM PM AM PM AM PM Week 1 // // // // // // // // // // // // // // Week 2 For the next 3 weeks, do not take any SPORANOX® capsules. Remember to get a refill before the end of Week 4 when your doctor prescribes another PulsePak® . Week 3 Week 4 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHAT ARE THE POSSIBLE SIDE EFFECTS OF SPORANOX®? The most common side effects that cause people to stop treatment either for a short time or completely include: skin rash, high triglyceride test results, high liver test results, and digestive system problems (such as nausea, bloating, and diarrhea). Stop SPORANOX® and call your doctor or get medical assistance right away if you have a severe allergic reaction. Symptoms of an allergic reaction may include skin rash, itching, hives, shortness of breath or difficulty breathing, and/or swelling of the face. Very rarely, an oversensitivity to sunlight, a tingling sensation in the limbs or a severe skin disorder can occur. If any of these symptoms occur, stop taking SPORANOX® and contact your doctor. Stop SPORANOX® and call your doctor right away if you develop shortness of breath; have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up white or pink phlegm; have unusual fast heartbeats; or begin to wake up at night. In rare cases, patients taking SPORANOX® could develop serious heart problems, and these could be warning signs of heart failure. Stop SPORANOX® and call your doctor right away if you become unusually tired; lose your appetite; or develop nausea, abdominal pain, or vomiting, a yellow color to your skin or eyes, or dark colored urine or pale stools (bowel movements). In rare cases, patients taking SPORANOX® could develop serious liver problems and these could be warning signs. Stop SPORANOX® and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking SPORANOX® have reported temporary or permanent hearing loss. Call your doctor right away if you develop tingling or numbness in your extremities (hands or feet), if your vision gets blurry or you see double, if you hear a ringing in your ears, if you lose the ability to control your urine or urinate much more than usual. Additional possible side effects include upset stomach, vomiting, abdominal pain, constipation, headache, menstrual disorders, erectile dysfunction, dizziness, muscle weakness or pain, painful joints, unpleasant taste, or hair loss. These are not all the side effects of SPORANOX®. Your doctor or pharmacist can give you a more complete list. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHAT SHOULD I DO IF I TAKE AN OVERDOSE OF SPORANOX®? If you think you took too much SPORANOX®, call your doctor or local poison control center, or go to the nearest hospital emergency room right away. HOW SHOULD I STORE SPORANOX® ? Keep all medicines, including SPORANOX®, out of the reach of children. Store SPORANOX® Capsules and the PulsePak® at room temperature in a dry place away from light. GENERAL ADVICE ABOUT SPORANOX® Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use SPORANOX® for a condition for which it was not prescribed. Do not give SPORANOX® to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about SPORANOX®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about SPORANOX® that is written for health professionals. You can also call 1-800-JANSSEN or visit the SPORANOX® Internet site at www.sporanox.com and the Janssen Internet site at www.us.janssen.com. This patient information has been approved by the U.S. Food and Drug Administration. The following are registered trademarks of their respective manufacturers: Mevacor® (Merck & Co., Inc.), Advicor® (Kos Pharmaceuticals, Inc.), Altocor™ (Andrx Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid® (Janssen Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis Pharmaceuticals Corporation), Methergine® (Novartis Pharmaceuticals Corporation), Orap® (Gate Pharmaceuticals), and Sular® (First Horizon Pharmaceutical Corporation) 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Corporate Logo © PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 [TBD] Printed in USA/ Revised [TBD] 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:42.244478	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020083s040s041s044lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 40}
12,195	SPORANOX® (itraconazole) Capsules Congestive Heart Failure: SPORANOX ® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX® Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) Drug Interactions: Coadministration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) with SPORANOX® (itraconazole) Capsules, Injection or Oral Solution is contraindicated SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine, concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information. DESCRIPTION SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1 ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one mixture with (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H 1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4 triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1 ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.) The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below: 50 mg (fed) 100 mg (fed) 100 mg (fasted) 200 mg (fed) Cmax (ng/mL) 45 ± 16* 132 ± 67 38 ± 20 289 ± 100 Tmax (hours) 3.2 ± 1.3 4.0 ± 1.1 3.3 ± 1.0 4.7 ± 1.4 AUC0-∞ (ng·h/mL) 567 ± 264 1899 ± 838 722 ± 289 5211 ± 2116 * mean ± standard deviation Doubling the SPORANOX® dose results in approximately a three-fold increase in the itraconazole plasma concentrations. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX® Capsules with or without a full meal: Itraconazole Hydroxyitraconazole Fed Fasted Fed Fasted Cmax (ng/mL) 239 ± 85* 140 ± 65 397 ± 103 286 ± 101 Tmax (hours) 4.5 ± 1.1 3.9 ± 1.0 5.1 ± 1.6 4.5 ± 1.1 AUC0-∞ (ng·h/mL) 3423 ± 1154 2094 ± 905 7978 ± 2648 5191 ± 2489 t1/2 (hours) 21 ± 5 21 ± 7 12 ± 3 12 ± 3 * mean ± standard deviation Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX® Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX® Capsules 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX® Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX® Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When SPORANOX® Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX® Capsules b.i.d. (with a full meal) for 15 days: Itraconazole Hydroxyitraconazole Cmax (ng/mL) 2282 ± 514* 3488 ± 742 Cmin (ng/mL) 1855 ± 535 3349 ± 761 Tmax (hours) 4.6 ± 1.8 3.4 ± 3.4 AUC0-12 h (ng·h/mL) 22569 ± 5375 38572 ± 8450 t1/2 (hours) 64 ± 32 56 ± 24 * mean ± standard deviation The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.) Special Populations: Renal Insufficiency: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Caution should be exercised when the drug is administered in this patient population. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Hepatic Insufficiency: Itraconazole is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. A pharmacokinetic study using a single oral 100 mg capsule dose of itraconazole was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half- life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of itraconazole. (See BOX WARNING, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX® Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX® Capsules, SPORANOX® should be discontinued. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum, Blastomyces dermatitidis, Zygomycete, Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species. Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV- infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail: Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX® Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX® Capsules b.i.d., followed by a 3 week period without SPORANOX®, which was followed by a second 1-week pulse of 200 mg 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda of SPORANOX® Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS Congestive Heart Failure: SPORANOX® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Post-marketing Experience.) Drug Interactions: Concomitant administration of SPORANOX® (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with SPORANOX®. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX®. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with SPORANOX®. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX® to patients with hypersensitivity to other azoles. WARNINGS SPORANOX® (itraconazole) Capsules and SPORANOX® Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Hepatic Effects: SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX® use or reinstitution of treatment with SPORANOX® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: SPORANOX® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX® therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX® Capsules, discontinue administration. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX® Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. SPORANOX® has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post- marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS General: SPORANOX® (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with Sporanox® treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox® is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Sporanox®. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Neuropathy: If neuropathy occurs that may be attributable to Sporanox® capsules, the treatment should be discontinued. Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions; CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Information for Patients: • The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used interchangeably with SPORANOX® Oral Solution. • Instruct patients to take SPORANOX® Capsules with a full meal. • Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX® administration, they should discontinue SPORANOX® and contact their healthcare provider immediately. • Instruct patients to stop SPORANOX® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. • Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (see Table 1 below and the following drug class subheadings that follow): 1. SPORANOX® may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX®. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX® therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. 2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX® may not be effective in patients concomitantly taking SPORANOX® and one of these drugs. Therefore, administration of these drugs with SPORANOX® is not recommended. 3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX®. Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by SPORANOX® 1 Drug plasma concentration increased by itraconazole Antiarrhythmics digoxin, dofetilide,2 quinidine,2 disopyramide Anticonvulsants carbamazepine Antimycobacterials rifabutin Antineoplastics busulfan, docetaxel, vinca alkaloids 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antipsychotics pimozide2 Benzodiazepines alprazolam, diazepam, midazolam,2, 3 triazolam2 Calcium Channel Blockers dihydropyridines (including nisoldipine2), verapamil Gastrointestinal Motility Agents cisapride2 HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2 Immunosuppressants cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics oral hypoglycemics Protease Inhibitors indinavir, ritonavir, saquinavir Other levacetylmethadol (levomethadyl),2 ergot alkaloids,2 halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl Decrease plasma concentration of itraconazole Anticonvulsants carbamazepine, phenobarbital, phenytoin Antimycobacterials isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors Non-nucleoside Reverse Transcriptase Inhibitors nevirapine Increase plasma concentration of itraconazole Macrolide Antibiotics clarithromycin, erythromycin Protease Inhibitors indinavir, ritonavir 1 This list is not all-inclusive. 2 Contraindicated with SPORANOX® based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) 3 For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX® may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and disopyramide are administered concomitantly. Concomitant administration of digoxin and SPORANOX® has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX® was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX® and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine. Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX® could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOX® may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Benzodiazepines: Concomitant administration of SPORANOX® and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX® and oral midazolam or triazolam is contraindicated. (See 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged. Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX® and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction, therefore the concomitant administration of SPORANOX® and nisoldipine is contraindicated. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX® Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX® should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX® Capsules. In a clinical study, when SPORANOX® Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. Gastrointestinal Motility Agents: Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX® inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX® with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOX® and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX® Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied. Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered. 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined. Protease Inhibitors: Concomitant administration of SPORANOX® and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX® and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX® and protease inhibitors must be given concomitantly. Other: • Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and levacetylmethadol is contraindicated. • Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with SPORANOX® is contraindicated. • Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and halofantrine are administered concomitantly. • In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX® may increase plasma concentrations of alfentanil. • Human pharmacokinetic data suggest that concomitant administration of SPORANOX® and buspirone results in significant increases in plasma concentrations of buspirone. • SPORANOX® may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone. • In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • SPORANOX enhances the anticoagulant effect of coumarin-like drugs, such as warfarin. • Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with SPORANOX®. • Fentanyl plasma concentrations could be increased or prolonged by concomitant use of SPORANOX® and may cause potentially fatal respiratory depression. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). 20 ® This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOX® therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-marketing Experience.) Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX® have not been established in pediatric patients. No pharmacokinetic data on SPORANOX® Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX® Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. Geriatric Use: Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). Itraconazole should be used with care in elderly patients (see PRECAUTIONS). HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX® use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.) 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea Vomiting Diarrhea Abdominal Pain Anorexia 11 5 3 2 1 Body as a Whole Edema Fatigue Fever Malaise 4 3 3 1 Skin and Appendages Rash* Pruritus 9 3 Central/Peripheral Nervous System Headache Dizziness 4 2 Psychiatric Libido Decreased Somnolence 1 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 * Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Post-marketing Experience Adverse drug reactions that have been identified during post-approval use of SPORANOX® (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Postmarketing Reports of Adverse Drug Reactions Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia Immune system disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Metabolism and nutrition disorders: Hypertriglyceridemia, hypokalemia Nervous system disorders: Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness Eye disorders: Visual disturbances, including vision blurred and diplopia Ear and labyrinth disorder: Transient or permanent hearing loss, tinnitus Cardiac disorders: Congestive heart failure Respiratory, thoracic and mediastinal disorders: Pulmonary edema Gastrointestinal disorders: Pancreatitis, abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia Hepato-biliary disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, pruritus 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Musculoskeletal and connective tissue disorders: Myalgia, arthralgia Renal and urinary disorders: Urinary incontinence, pollakiuria Reproductive system and breast disorders: Menstrual disorders, erectile dysfunction General disorders and administration site conditions: Peripheral edema, pyrexia There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX® has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.) OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX® (itraconazole) Oral Solution or up to 3000 mg of SPORANOX® (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses. DOSAGE AND ADMINISTRATION SPORANOX® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX® Capsules is a different preparation than SPORANOX® Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously. • IV Injection: the recommended intravenous dose is 200 mg b.i.d. for four consecutive doses, followed by 200 mg once daily thereafter. Each intravenous dose should be infused over 1 hour. The safety and efficacy of SPORANOX® Injection administered for greater than 14 days is not known. See complete prescribing information for SPORANOX® (itraconazole) Injection. • Capsules: although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX® Capsules and SPORANOX® Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX®. Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS for further information.) 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use in Patients with Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.) HOW SUPPLIED SPORANOX® (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 × 10 capsules (NDC 50458-290 01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs × 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children. © Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2001 U.S. Patent Nos. 4,267,179; 5,633,015 Revised November 2009 Capsule contents manufactured by: Janssen Pharmaceutica N.V. Olen, Belgium Manufactured by: JOLLC, Gurabo, Puerto Rico 00778 Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION 100 mg SPORANOX® (itraconazole) Capsules This summary contains important information about SPORANOX® (SPOR-ah-nox). This information is for patients who have been prescribed SPORANOX® to treat fungal nail infections. If your doctor prescribed SPORANOX® for medical problems other than fungal nail infections, ask your doctor if there is any information in this summary that does not apply to you. Read this information carefully each time you start to use SPORANOX®. This information does not take the place of discussion between you and your doctor. Only your doctor can decide if SPORANOX® is the right treatment for you. If you do not understand some of this information or have any questions, talk with your doctor or pharmacist. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT SPORANOX®? SPORANOX® is used to treat fungal nail infections. However, SPORANOX® is not for everyone. Do not take SPORANOX® for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take SPORANOX® if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See “Who Should Not Take SPORANOX®?” below.) If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is safe for you to take SPORANOX®. WHAT HAPPENS IF I HAVE A FUNGAL NAIL INFECTION? Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort. WHAT IS SPORANOX®? SPORANOX® is a prescription medicine used to treat fungal infections of the toenails and fingernails. It is also used to treat some types of fungal infections in other areas of your body. 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda We do not know if SPORANOX® works in children with fungal nail infections or if it is safe for children to take. SPORANOX® comes in the form of capsules and liquid (oral solution). The capsule and liquid forms work differently, so you should not use one in place of the other. This Patient Information discusses only the capsule form of SPORANOX®. You will get these capsules in a medicine bottle or a SPORANOX PulsePak®. The PulsePak® contains 28 capsules for treatment of your fungal nail infection. SPORANOX® goes into your bloodstream and travels to the source of the infection underneath the nail so that it can fight the infection there. Improved nails may not be obvious for several months after the treatment period is finished because it usually takes about 6 months to grow a new fingernail and 12 months to grow a new toenail. WHO SHOULD NOT TAKE SPORANOX®? SPORANOX® is not for everyone. Your doctor will decide if SPORANOX® is the right treatment for you. Some patients should not take SPORANOX® because they may have certain health problems or may be taking certain medicines that could lead to serious or life-threatening medical problems. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking, including dietary supplements and herbal remedies. Also tell your doctor about any other medical conditions you have had, especially heart, lung, liver or kidney conditions. Never take SPORANOX® if you: • have had heart failure, including congestive heart failure. • are taking any of the medicines listed below. Dangerous or even life-threatening abnormal heartbeats could result: • quinidine (such as Cardioquin®, Quinaglute®, Quinidex®) • dofetilide (such as Tikosyn™) • cisapride (such as Propulsid®) • pimozide (such as Orap®) • levacetylmethadol (such as Orlaam®) • are taking any of the following medicines: 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • lovastatin (such as Mevacor®, Advicor®, Altocor™) • simvastatin (such as Zocor®) • triazolam (such as Halcion®) • midazolam (such as Versed®) • nisoldipine (such as Sular®) • ergot alkaloids (such as Migranal®, Ergonovine, Cafergot®, Methergine®) • have ever had an allergic reaction to itraconazole or any of the other ingredients in SPORANOX Capsules. Ask your doctor or pharmacist for a list of these ingredients. Taking SPORANOX® with certain other medicines could lead to serious or life-threatening medical problems. For example, taking fentanyl, a strong opioid narcotic pain medicine, with SPORANOX® could cause serious side effects, including trouble breathing, that may be life- threatening. Tell your doctor and pharmacist the name of all the prescription and non prescription medicines you are taking. Your doctor will decide if SPORANOX® is the right treatment for you. WHAT SHOULD I KNOW ABOUT SPORANOX® AND PREGNANCY OR BREAST FEEDING? Never take SPORANOX® if you have a fungal nail infection and are pregnant or planning to become pregnant within 2 months after you have finished your treatment. If you are able to become pregnant, you should use effective birth control during SPORANOX® treatment and for 2 months after finishing treatment. Ask your doctor about effective types of birth control. If you are breast-feeding, talk with your doctor about whether you should take SPORANOX®. HOW SHOULD I TAKE SPORANOX®? Always take SPORANOX® Capsules during or right after a full meal. Your doctor will decide the right dose for you. Depending on your infection, you will take SPORANOX® once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing schedule. You will receive either a bottle of capsules or a PulsePak®. Do not skip any doses. Be sure to finish all your SPORANOX® as prescribed by your doctor. 31 ® This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven’t had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking SPORANOX® can develop liver problems. If you forget to take or miss doses of SPORANOX®, ask your doctor what you should do with the missed doses. THE SPORANOX PulsePak® If you use the PulsePak®, you will take SPORANOX® for 1 week and then take no SPORANOX® for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The SPORANOX PulsePak® contains enough medicine for one “pulse” (1 week of treatment). The SPORANOX PulsePak® comes with special instructions. It contains 7 pouches-one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of the card, fold it back along the dashed line and peel away the backing so that you can remove 2 capsules. • Take 2 capsules in the morning and 2 capsules in the evening. This means you will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all of the capsules in the PulsePak® box. • After you finish the PulsePak®, do not take any SPORANOX for the next 3 weeks. Even though you are not taking any capsules during this time, ® SPORANOX keeps working inside your nails to help fight the fungal infection. • You will need more than one “pulse” to treat your fungal nail infection. When your doctor prescribes another pulse treatment, be sure to get your refill before the end of week 4. SPORANOX® Pulse Dosing Take 2 SPORANOX® capsules twice a day for 1 week Day1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 AM PM AM PM AM PM AM PM AM PM AM PM AM PM Week 1 // // // // // // // // // // // // // // Week 2 For the next 3 weeks, do not take any SPORANOX® capsules. Week 3 32 ® This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda table WHAT ARE THE POSSIBLE SIDE EFFECTS OF SPORANOX®? The most common side effects that cause people to stop treatment either for a short time or completely include: skin rash, high triglyceride test results, high liver test results, and digestive system problems (such as nausea, bloating, and diarrhea). Stop SPORANOX® and call your doctor or get medical assistance right away if you have a severe allergic reaction. Symptoms of an allergic reaction may include skin rash, itching, hives, shortness of breath or difficulty breathing, and/or swelling of the face. Very rarely, an oversensitivity to sunlight, a tingling sensation in the limbs or a severe skin disorder can occur. If any of these symptoms occur, stop taking SPORANOX® and contact your doctor. Stop SPORANOX® and call your doctor right away if you develop shortness of breath; have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up white or pink phlegm; have unusual fast heartbeats; or begin to wake up at night. In rare cases, patients taking SPORANOX® could develop serious heart problems, and these could be warning signs of heart failure. Stop SPORANOX® and call your doctor right away if you become unusually tired; lose your appetite; or develop nausea, abdominal pain, or vomiting, a yellow color to your skin or eyes, or dark colored urine or pale stools (bowel movements). In rare cases, patients taking SPORANOX® could develop serious liver problems and these could be warning signs. Stop SPORANOX® and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking SPORANOX® have reported temporary or permanent hearing loss. Call your doctor right away if you develop tingling or numbness in your extremities (hands or feet), if your vision gets blurry or you see double, if you hear a ringing in your ears, if you lose the ability to control your urine or urinate much more than usual. Additional possible side effects include upset stomach, vomiting, abdominal pain, constipation, headache, fever, inflammation of the pancreas, menstrual disorders, erectile dysfunction, dizziness, muscle weakness or pain, painful joints, unpleasant taste, or hair loss. These are not all the side effects of SPORANOX®. Your doctor or pharmacist can give you a more complete list. 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHAT SHOULD I DO IF I TAKE AN OVERDOSE OF SPORANOX®? If you think you took too much SPORANOX®, call your doctor or local poison control center, or go to the nearest hospital emergency room right away. HOW SHOULD I STORE SPORANOX®? Keep all medicines, including SPORANOX®, out of the reach of children. Store SPORANOX® Capsules and the PulsePak® at room temperature in a dry place away from light. GENERAL ADVICE ABOUT SPORANOX® Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use SPORANOX® for a condition for which it was not prescribed. Do not give SPORANOX® to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about SPORANOX®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about SPORANOX® that is written for health professionals or you can call 1-800 526-7736. This patient information has been approved by the U.S. Food and Drug Administration. The following are registered trademarks of their respective manufacturers: Mevacor® (Merck & Co., Inc.), Advicor® (Kos Pharmaceuticals, Inc.), Altocor™ (Andrx Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid® (Janssen Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis Pharmaceuticals Corporation), Methergine® (Novartis Pharmaceuticals Corporation), Orap® (Gate Pharmaceuticals), and Sular® (Sciele Pharma, Inc.) Corporate Logo © Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2001 Printed in USA/ Revised: November 2009 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:42.421791	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020083s046lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 46}
12,196	structural formula SPORANOX® (itraconazole) Capsules Congestive Heart Failure, Cardiac Effects and Drug Interactions: SPORANOX ® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX® Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions: Coadministration of cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with SPORANOX® (itraconazole) Capsules or Oral Solution is contraindicated. SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, methadone, levacetylmethadol (levomethadyl), or quinidine, concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information. DESCRIPTION SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: 1 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1 ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one mixture with (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H 1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4 triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1 ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.) The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below: 2 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50 mg (fed) 100 mg (fed) 100 mg (fasted) 200 mg (fed) Cmax (ng/mL) 45 ± 16* 132 ± 67 38 ± 20 289 ± 100 Tmax (hours) 3.2 ± 1.3 4.0 ± 1.1 3.3 ± 1.0 4.7 ± 1.4 AUC0-∞ (ng·h/mL) 567 ± 264 1899 ± 838 722 ± 289 5211 ± 2116 * mean ± standard deviation Doubling the SPORANOX® dose results in approximately a three-fold increase in the itraconazole plasma concentrations in the dose range of 50 mg to 200 mg. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX® Capsules with or without a full meal: Itraconazole Hydroxyitraconazole Fed Fasted Fed Fasted Cmax (ng/mL) 239 ± 85* 140 ± 65 397 ± 103 286 ± 101 Tmax (hours) 4.5 ± 1.1 3.9 ± 1.0 5.1 ± 1.6 4.5 ± 1.1 AUC0-∞ (ng·h/mL) 3423 ± 1154 2094 ± 905 7978 ± 2648 5191 ± 2489 t1/2 (hours) 21 ± 5 21 ± 7 12 ± 3 12 ± 3 * mean ± standard deviation Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX® Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX® Capsules were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX® Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX® Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When SPORANOX® Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed 3 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX® Capsules b.i.d. (with a full meal) for 15 days: Itraconazole Hydroxyitraconazole Cmax (ng/mL) 2282 ± 514* 3488 ± 742 Cmin (ng/mL) 1855 ± 535 3349 ± 761 Tmax (hours) 4.6 ± 1.8 3.4 ± 3.4 AUC0-12 h (ng·h/mL) 22569 ± 5375 38572 ± 8450 t1/2 (hours) 64 ± 32 56 ± 24 * mean ± standard deviation The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.) Special Populations: Renal Insufficiency: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of 4 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Caution should be exercised when the drug is administered in this patient population. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Hepatic Insufficiency: Itraconazole is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. A pharmacokinetic study using a single oral 100-mg capsule dose of itraconazole was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half- life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of itraconazole. (See BOX WARNING, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX® Capsules, SPORANOX® should be discontinued. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. 5 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum, Blastomyces dermatitidis, Zygomycete, Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species. Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. 6 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) 7 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV- infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail: Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX® Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative 8 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX® Capsules b.i.d., followed by a 3 week period without SPORANOX®, which was followed by a second 1-week pulse of 200 mg of SPORANOX® Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS Congestive Heart Failure: SPORANOX® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See WARNINGS, PRECAUTIONS: Drug Interactions- Calcium Channel Blockers, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations.) Drug Interactions: Concomitant administration of SPORANOX® (itraconazole) Capsules or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, methadone and levacetylmethadol (levomethadyl) are contraindicated with SPORANOX®. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX®. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with SPORANOX®. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) 9 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX® to patients with hypersensitivity to other azoles. WARNINGS SPORANOX® (itraconazole) Capsules and SPORANOX® Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Hepatic Effects: SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX® use or reinstitution of treatment with SPORANOX® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, methadone, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: SPORANOX® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. 10 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX® therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX® Capsules, discontinue administration. Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. SPORANOX® has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post- marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS General: SPORANOX® (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. 11 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with SPORANOX® treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX® is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving SPORANOX®. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Neuropathy: If neuropathy occurs that may be attributable to SPORANOX® Capsules, the treatment should be discontinued. Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions; CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Information for Patients:  The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used interchangeably with SPORANOX® Oral Solution.  Instruct patients to take SPORANOX® Capsules with a full meal.  Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX® administration, they should discontinue SPORANOX® and contact their healthcare provider immediately.  Instruct patients to stop SPORANOX® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.  Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Reference ID: 3118502 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (see Table 1 below and the drug class subheadings that follow): 1. SPORANOX® may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX®. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX® therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. 2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX® may not be effective in patients concomitantly taking SPORANOX® and one of these drugs. Therefore, administration of these drugs with SPORANOX® is not recommended. 3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX®. Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by SPORANOX® 1 Drug plasma concentration increased by itraconazole Antiarrhythmics digoxin, dofetilide,2 quinidine,2 disopyramide Anticonvulsants carbamazepine Antimycobacterials rifabutin Antineoplastics busulfan, docetaxel, vinca alkaloids Antipsychotics pimozide2 13 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by SPORANOX® 1 Benzodiazepines alprazolam, diazepam, midazolam,2, 3 triazolam2 Calcium Channel Blockers dihydropyridines (including felodipine2 and nisoldipine2), verapamil Gastrointestinal Motility Agents cisapride2 HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2 Immunosuppressants cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics oral hypoglycemics Protease Inhibitors indinavir, ritonavir, saquinavir Other methadone,2 levacetylmethadol (levomethadyl),2 ergot alkaloids,2 halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl Decrease plasma concentration of itraconazole Anticonvulsants carbamazepine, phenobarbital, phenytoin Antimycobacterials isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors Non-nucleoside Reverse Transcriptase Inhibitors nevirapine Increase plasma concentration of itraconazole Macrolide Antibiotics clarithromycin, erythromycin Protease Inhibitors indinavir, ritonavir 1 This list is not all-inclusive. 2 Contraindicated with SPORANOX® based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) 3 For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX® may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and disopyramide are administered concomitantly. Concomitant administration of digoxin and SPORANOX® has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein. 14 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX® was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX® and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine. Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX® could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOX® may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Benzodiazepines: Concomitant administration of SPORANOX® and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX® and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring are required since the sedative effect may be prolonged. Reference ID: 3118502 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX® and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine, nisoldipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction. Therefore the concomitant administration of SPORANOX® and nisoldipine is contraindicated. A clinical study showed that felodipine exposure was increased by coadministration of itraconazole, resulting in approximately a 6-fold increase in the AUC and an 8-fold increase in the Cmax. The concomitant use of SPORANOX® and felodipine is contraindicated. (See CONTRAINDICATIONS, WARNINGS, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX® Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX® should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX® Capsules. In a clinical study, when SPORANOX® Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. Gastrointestinal Motility Agents: Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX® inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX® with 16 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOX® and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX® Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied. Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered. Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined. 17 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Protease Inhibitors: Concomitant administration of SPORANOX® and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX® and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX® and protease inhibitors must be given concomitantly. Other:  Methadone and levacetylmethadol (levomethadyl) are known to prolong the QT interval and are metabolized by CYP3A4. Co-administration of methadone or levacetylmethadol with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and methadone or levacetylmethadol is contraindicated.  Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with SPORANOX® is contraindicated.  Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and halofantrine are administered concomitantly.  In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX® may increase plasma concentrations of alfentanil.  Human pharmacokinetic data suggest that concomitant administration of SPORANOX® and buspirone results in significant increases in plasma concentrations of buspirone.  SPORANOX® may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone.  In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and trimetrexate may inhibit the metabolism of trimetrexate.  SPORANOX® enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.  Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with SPORANOX®.  Fentanyl plasma concentrations could be increased or prolonged by concomitant use of SPORANOX® and may cause potentially fatal respiratory depression. 18 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day 19 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda following the onset of menses. Effective contraception should be continued throughout SPORANOX® therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-marketing Experience.) Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX® have not been established in pediatric patients. No pharmacokinetic data on SPORANOX® Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX® Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. Geriatric Use: Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). Itraconazole should be used with care in elderly patients (see PRECAUTIONS). HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. Reference ID: 3118502 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX® use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea Vomiting Diarrhea Abdominal Pain Anorexia 11 5 3 2 1 Body as a Whole Edema Fatigue Fever Malaise 4 3 3 1 21 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Skin and Appendages Rash* Pruritus 9 3 Central/Peripheral Nervous System Headache Dizziness 4 2 Psychiatric Libido Decreased Somnolence 1 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 * Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 22 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Post-marketing Experience Adverse drug reactions that have been identified during post-approval use of SPORANOX® (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. 23 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Postmarketing Reports of Adverse Drug Reactions Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia Immune system disorders: Metabolism and nutrition disorders: Nervous system disorders: Eye disorders: Ear and labyrinth disorders: Cardiac disorders: Respiratory, thoracic and mediastinal disorders: Gastrointestinal disorders: Hepato-biliary disorders: Skin and subcutaneous tissue disorders: Musculoskeletal and connective tissue disorders: Renal and urinary disorders: Reproductive system and breast disorders: General disorders and administration site conditions: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Hypertriglyceridemia, hypokalemia Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness Visual disturbances, including vision blurred and diplopia Transient or permanent hearing loss, tinnitus Congestive heart failure Pulmonary edema, dyspnea Pancreatitis, abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, pruritus Myalgia, arthralgia Urinary incontinence, pollakiuria Menstrual disorders, erectile dysfunction Peripheral edema, pyrexia There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX® has not been established. Reference ID: 3118502 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.) OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX® (itraconazole) Oral Solution or up to 3000 mg of SPORANOX® (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses. DOSAGE AND ADMINISTRATION SPORANOX® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX® Capsules is a different preparation than SPORANOX® Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used. Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX® Capsules and SPORANOX® Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. 25 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX®. Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS for further information.) Use in Patients with Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.) HOW SUPPLIED SPORANOX® (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 × 10 capsules (NDC 50458-290 01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs × 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children. © Ortho-McNeil-Janssen Pharmaceuticals, Inc 2001 Revised April 2012 Capsule contents manufactured by: Janssen Pharmaceutica N.V. Olen, Belgium Manufactured by: 26 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda JOLLC, Gurabo, Puerto Rico 00778 Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 27 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION 100 mg SPORANOX® (itraconazole) Capsules This summary contains important information about SPORANOX® (SPOR-ah-nox). This information is for patients who have been prescribed SPORANOX® to treat fungal nail infections. If your doctor prescribed SPORANOX® for medical problems other than fungal nail infections, ask your doctor if there is any information in this summary that does not apply to you. Read this information carefully each time you start to use SPORANOX®. This information does not take the place of discussion between you and your doctor. Only your doctor can decide if SPORANOX® is the right treatment for you. If you do not understand some of this information or have any questions, talk with your doctor or pharmacist. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT SPORANOX®? SPORANOX® is used to treat fungal nail infections. However, SPORANOX® is not for everyone. Do not take SPORANOX® for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take SPORANOX® if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See “Who Should Not Take SPORANOX®?” below.) If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is safe for you to take SPORANOX®. WHAT HAPPENS IF I HAVE A FUNGAL NAIL INFECTION? Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort. WHAT IS SPORANOX®? SPORANOX® is a prescription medicine used to treat fungal infections of the toenails and fingernails. It is also used to treat some types of fungal infections in other areas of your body. We do not know if SPORANOX® works in children with fungal nail infections or if it is safe for children to take. 28 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX® comes in the form of capsules and liquid (oral solution). The capsule and liquid forms work differently, so you should not use one in place of the other. This Patient Information discusses only the capsule form of SPORANOX®. You will get these capsules in a medicine bottle or a SPORANOX PulsePak®. The PulsePak® contains 28 capsules for treatment of your fungal nail infection. SPORANOX® goes into your bloodstream and travels to the source of the infection underneath the nail so that it can fight the infection there. Improved nails may not be obvious for several months after the treatment period is finished because it usually takes about 6 months to grow a new fingernail and 12 months to grow a new toenail. WHO SHOULD NOT TAKE SPORANOX®? SPORANOX® is not for everyone. Your doctor will decide if SPORANOX® is the right treatment for you. Some patients should not take SPORANOX® because they may have certain health problems or may be taking certain medicines that could lead to serious or life-threatening medical problems. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking, including dietary supplements and herbal remedies. Also tell your doctor about any other medical conditions you have had, especially heart, lung, liver or kidney conditions. Never take SPORANOX® if you:  have had heart failure, including congestive heart failure.  are taking any of the medicines listed below. Dangerous or even life-threatening abnormal heartbeats could result:  quinidine (such as Cardioquin®, Quinaglute®, Quinidex®)  dofetilide (such as Tikosyn™)  cisapride (such as Propulsid®)  pimozide (such as Orap®)  methadone (such as Dolophine®)  levacetylmethadol (such as Orlaam®)  are taking any of the following medicines:  lovastatin (such as Mevacor®, Advicor®, Altocor™)  simvastatin (such as Zocor®)  triazolam (such as Halcion®) 29 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  midazolam (such as Versed®)  nisoldipine (such as Sular®)  felodipine (such as Plendil®)  ergot alkaloids (such as Migranal®, Ergonovine, Cafergot®, Methergine®)  have ever had an allergic reaction to itraconazole or any of the other ingredients in SPORANOX® Capsules. Ask your doctor or pharmacist for a list of these ingredients. Taking SPORANOX® with certain other medicines could lead to serious or life-threatening medical problems. For example, taking fentanyl, a strong opioid narcotic pain medicine, with SPORANOX® could cause serious side effects, including trouble breathing, that may be life- threatening. Tell your doctor and pharmacist the name of all the prescription and non prescription medicines you are taking. Your doctor will decide if SPORANOX® is the right treatment for you. WHAT SHOULD I KNOW ABOUT SPORANOX® AND PREGNANCY OR BREAST FEEDING? Never take SPORANOX® if you have a fungal nail infection and are pregnant or planning to become pregnant within 2 months after you have finished your treatment. If you are able to become pregnant, you should use effective birth control during SPORANOX® treatment and for 2 months after finishing treatment. Ask your doctor about effective types of birth control. If you are breast-feeding, talk with your doctor about whether you should take SPORANOX®. HOW SHOULD I TAKE SPORANOX®? Always take SPORANOX® Capsules during or right after a full meal. Your doctor will decide the right dose for you. Depending on your infection, you will take SPORANOX® once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing schedule. You will receive either a bottle of capsules or a PulsePak®. Do not skip any doses. Be sure to finish all your SPORANOX® as prescribed by your doctor. If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven’t had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking SPORANOX® can develop liver problems. If you forget to take or miss doses of SPORANOX®, ask your doctor what you should do with the missed doses. 30 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda THE SPORANOX PULSEPAK® If you use the PulsePak®, you will take SPORANOX® for 1 week and then take no SPORANOX® for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The SPORANOX PulsePak® contains enough medicine for one “pulse” (1 week of treatment). The SPORANOX PulsePak® comes with special instructions. It contains 7 pouches-one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of the card, fold it back along the dashed line and peel away the backing so that you can remove 2 capsules.  Take 2 capsules in the morning and 2 capsules in the evening. This means you will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all of the capsules in the PulsePak® box.  After you finish the PulsePak®, do not take any SPORANOX® for the next 3 weeks. Even though you are not taking any capsules during this time, SPORANOX® keeps working inside your nails to help fight the fungal infection.  You will need more than one “pulse” to treat your fungal nail infection. When your doctor prescribes another pulse treatment, be sure to get your refill before the end of week 4. SPORANOX® Pulse Dosing Take 2 SPORANOX® capsules twice a day for 1 week Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 AM PM AM PM AM PM AM PM AM PM AM PM AM PM Week 1 // // // // // // // // // // // // // // Week 2 For the next 3 weeks, do not take any SPORANOX® capsules. Remember to get a refill before the end of Week 4 when your doctor prescribes another PulsePak® . Week 3 Week 4 WHAT ARE THE POSSIBLE SIDE EFFECTS OF SPORANOX®? The most common side effects that cause people to stop treatment either for a short time or completely include: skin rash, high triglyceride test results, high liver test results, and digestive system problems (such as nausea, bloating, and diarrhea). Stop SPORANOX® and call your doctor or get medical assistance right away if you have a severe allergic reaction. Symptoms of an allergic reaction may include skin rash, itching, hives, 31 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda shortness of breath or difficulty breathing, and/or swelling of the face. Very rarely, an oversensitivity to sunlight, a tingling sensation in the limbs or a severe skin disorder can occur. If any of these symptoms occur, stop taking SPORANOX® and contact your doctor. Stop SPORANOX® and call your doctor right away if you develop shortness of breath; have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up white or pink phlegm; have unusual fast heartbeats; or begin to wake up at night. In rare cases, patients taking SPORANOX® could develop serious heart problems, and these could be warning signs of heart failure. Stop SPORANOX® and call your doctor right away if you become unusually tired; lose your appetite; or develop nausea, abdominal pain, or vomiting, a yellow color to your skin or eyes, or dark colored urine or pale stools (bowel movements). In rare cases, patients taking SPORANOX® could develop serious liver problems and these could be warning signs. Stop SPORANOX® and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking SPORANOX® have reported temporary or permanent hearing loss. Call your doctor right away if you develop tingling or numbness in your extremities (hands or feet), if your vision gets blurry or you see double, if you hear a ringing in your ears, if you lose the ability to control your urine or urinate much more than usual. Additional possible side effects include upset stomach, vomiting, abdominal pain, constipation, headache, fever, inflammation of the pancreas, menstrual disorders, erectile dysfunction, dizziness, muscle weakness or pain, painful joints, unpleasant taste, or hair loss. These are not all the side effects of SPORANOX®. Your doctor or pharmacist can give you a more complete list. WHAT SHOULD I DO IF I TAKE AN OVERDOSE OF SPORANOX®? If you think you took too much SPORANOX®, call your doctor or local poison control center, or go to the nearest hospital emergency room right away. HOW SHOULD I STORE SPORANOX®? Keep all medicines, including SPORANOX®, out of the reach of children. Store SPORANOX® Capsules and the PulsePak® at room temperature in a dry place away from light. 32 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda GENERAL ADVICE ABOUT SPORANOX® Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use SPORANOX® for a condition for which it was not prescribed. Do not give SPORANOX® to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about SPORANOX®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about SPORANOX® that is written for health professionals or you can call 1-800 526-7736. This patient information has been approved by the U.S. Food and Drug Administration. The following are registered trademarks of their respective manufacturers: Mevacor® (Merck & Co., Inc.), Advicor® (Kos Pharmaceuticals, Inc.), Altocor™ (Andrx Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid® (Janssen Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis Pharmaceuticals Corporation), Methergine® (Novartis Pharmaceuticals Corporation), Orap® (Gate Pharmaceuticals), Sular® (Sciele Pharma, Inc.), Dolophine® (PD-Rx Pharmaceuticals, Inc), and Plendil® (AstraZeneca LP). Corporate Logo © Ortho-McNeil-Janssen Pharmaceuticals, Inc 2001 Printed in USA/ Revised: April 2012 33 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:42.579005	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020083s048s049s050lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 48}
12,197	structural formula SPORANOX® (itraconazole) Capsules Congestive Heart Failure, Cardiac Effects and Drug Interactions: SPORANOX ® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX® Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions: Coadministration of cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with SPORANOX® (itraconazole) Capsules or Oral Solution is contraindicated. SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, methadone, levacetylmethadol (levomethadyl), or quinidine, concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information. DESCRIPTION SPORANOX® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: 1 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1 ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one mixture with (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H 1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4 triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1 ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.) The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below: 2 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50 mg (fed) 100 mg (fed) 100 mg (fasted) 200 mg (fed) Cmax (ng/mL) 45 ± 16* 132 ± 67 38 ± 20 289 ± 100 Tmax (hours) 3.2 ± 1.3 4.0 ± 1.1 3.3 ± 1.0 4.7 ± 1.4 AUC0-∞ (ng·h/mL) 567 ± 264 1899 ± 838 722 ± 289 5211 ± 2116 * mean ± standard deviation Doubling the SPORANOX® dose results in approximately a three-fold increase in the itraconazole plasma concentrations in the dose range of 50 mg to 200 mg. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX® Capsules with or without a full meal: Itraconazole Hydroxyitraconazole Fed Fasted Fed Fasted Cmax (ng/mL) 239 ± 85* 140 ± 65 397 ± 103 286 ± 101 Tmax (hours) 4.5 ± 1.1 3.9 ± 1.0 5.1 ± 1.6 4.5 ± 1.1 AUC0-∞ (ng·h/mL) 3423 ± 1154 2094 ± 905 7978 ± 2648 5191 ± 2489 t1/2 (hours) 21 ± 5 21 ± 7 12 ± 3 12 ± 3 * mean ± standard deviation Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX® Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX® Capsules were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX® Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX® Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When SPORANOX® Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed 3 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX® Capsules b.i.d. (with a full meal) for 15 days: Itraconazole Hydroxyitraconazole Cmax (ng/mL) 2282 ± 514* 3488 ± 742 Cmin (ng/mL) 1855 ± 535 3349 ± 761 Tmax (hours) 4.6 ± 1.8 3.4 ± 3.4 AUC0-12 h (ng·h/mL) 22569 ± 5375 38572 ± 8450 t1/2 (hours) 64 ± 32 56 ± 24 * mean ± standard deviation The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.) Special Populations: Renal Insufficiency: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of 4 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Caution should be exercised when the drug is administered in this patient population. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Hepatic Insufficiency: Itraconazole is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. A pharmacokinetic study using a single oral 100-mg capsule dose of itraconazole was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half- life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of itraconazole. (See BOX WARNING, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX® Capsules, SPORANOX® should be discontinued. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. 5 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum, Blastomyces dermatitidis, Zygomycete, Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species. Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. 6 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) 7 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV- infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail: Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX® Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative 8 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX® Capsules b.i.d., followed by a 3 week period without SPORANOX®, which was followed by a second 1-week pulse of 200 mg of SPORANOX® Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS Congestive Heart Failure: SPORANOX® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See WARNINGS, PRECAUTIONS: Drug Interactions- Calcium Channel Blockers, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations.) Drug Interactions: Concomitant administration of SPORANOX® (itraconazole) Capsules or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, methadone and levacetylmethadol (levomethadyl) are contraindicated with SPORANOX®. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX®. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with SPORANOX®. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) 9 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX® to patients with hypersensitivity to other azoles. WARNINGS SPORANOX® (itraconazole) Capsules and SPORANOX® Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Hepatic Effects: SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX® use or reinstitution of treatment with SPORANOX® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, methadone, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: SPORANOX® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. 10 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX® therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX® Capsules, discontinue administration. Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. SPORANOX® has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post- marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS General: SPORANOX® (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. 11 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with SPORANOX® treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX® is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving SPORANOX®. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Neuropathy: If neuropathy occurs that may be attributable to SPORANOX® Capsules, the treatment should be discontinued. Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions; CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Information for Patients:  The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used interchangeably with SPORANOX® Oral Solution.  Instruct patients to take SPORANOX® Capsules with a full meal.  Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX® administration, they should discontinue SPORANOX® and contact their healthcare provider immediately.  Instruct patients to stop SPORANOX® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.  Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Reference ID: 3118502 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (see Table 1 below and the drug class subheadings that follow): 1. SPORANOX® may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX®. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX® therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. 2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX® may not be effective in patients concomitantly taking SPORANOX® and one of these drugs. Therefore, administration of these drugs with SPORANOX® is not recommended. 3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX®. Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by SPORANOX® 1 Drug plasma concentration increased by itraconazole Antiarrhythmics digoxin, dofetilide,2 quinidine,2 disopyramide Anticonvulsants carbamazepine Antimycobacterials rifabutin Antineoplastics busulfan, docetaxel, vinca alkaloids Antipsychotics pimozide2 13 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by SPORANOX® 1 Benzodiazepines alprazolam, diazepam, midazolam,2, 3 triazolam2 Calcium Channel Blockers dihydropyridines (including felodipine2 and nisoldipine2), verapamil Gastrointestinal Motility Agents cisapride2 HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2 Immunosuppressants cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics oral hypoglycemics Protease Inhibitors indinavir, ritonavir, saquinavir Other methadone,2 levacetylmethadol (levomethadyl),2 ergot alkaloids,2 halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl Decrease plasma concentration of itraconazole Anticonvulsants carbamazepine, phenobarbital, phenytoin Antimycobacterials isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors Non-nucleoside Reverse Transcriptase Inhibitors nevirapine Increase plasma concentration of itraconazole Macrolide Antibiotics clarithromycin, erythromycin Protease Inhibitors indinavir, ritonavir 1 This list is not all-inclusive. 2 Contraindicated with SPORANOX® based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) 3 For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX® may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and disopyramide are administered concomitantly. Concomitant administration of digoxin and SPORANOX® has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein. 14 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX® was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX® and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine. Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX® could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOX® may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Benzodiazepines: Concomitant administration of SPORANOX® and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX® and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring are required since the sedative effect may be prolonged. Reference ID: 3118502 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX® and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine, nisoldipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction. Therefore the concomitant administration of SPORANOX® and nisoldipine is contraindicated. A clinical study showed that felodipine exposure was increased by coadministration of itraconazole, resulting in approximately a 6-fold increase in the AUC and an 8-fold increase in the Cmax. The concomitant use of SPORANOX® and felodipine is contraindicated. (See CONTRAINDICATIONS, WARNINGS, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX® Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX® should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX® Capsules. In a clinical study, when SPORANOX® Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. Gastrointestinal Motility Agents: Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX® inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX® with 16 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOX® and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX® Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied. Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered. Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined. 17 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Protease Inhibitors: Concomitant administration of SPORANOX® and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX® and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX® and protease inhibitors must be given concomitantly. Other:  Methadone and levacetylmethadol (levomethadyl) are known to prolong the QT interval and are metabolized by CYP3A4. Co-administration of methadone or levacetylmethadol with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and methadone or levacetylmethadol is contraindicated.  Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with SPORANOX® is contraindicated.  Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and halofantrine are administered concomitantly.  In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX® may increase plasma concentrations of alfentanil.  Human pharmacokinetic data suggest that concomitant administration of SPORANOX® and buspirone results in significant increases in plasma concentrations of buspirone.  SPORANOX® may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone.  In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and trimetrexate may inhibit the metabolism of trimetrexate.  SPORANOX® enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.  Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with SPORANOX®.  Fentanyl plasma concentrations could be increased or prolonged by concomitant use of SPORANOX® and may cause potentially fatal respiratory depression. 18 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day 19 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda following the onset of menses. Effective contraception should be continued throughout SPORANOX® therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-marketing Experience.) Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX® have not been established in pediatric patients. No pharmacokinetic data on SPORANOX® Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX® Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. Geriatric Use: Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). Itraconazole should be used with care in elderly patients (see PRECAUTIONS). HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. Reference ID: 3118502 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX® use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea Vomiting Diarrhea Abdominal Pain Anorexia 11 5 3 2 1 Body as a Whole Edema Fatigue Fever Malaise 4 3 3 1 21 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Skin and Appendages Rash* Pruritus 9 3 Central/Peripheral Nervous System Headache Dizziness 4 2 Psychiatric Libido Decreased Somnolence 1 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 * Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 22 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Post-marketing Experience Adverse drug reactions that have been identified during post-approval use of SPORANOX® (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. 23 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Postmarketing Reports of Adverse Drug Reactions Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia Immune system disorders: Metabolism and nutrition disorders: Nervous system disorders: Eye disorders: Ear and labyrinth disorders: Cardiac disorders: Respiratory, thoracic and mediastinal disorders: Gastrointestinal disorders: Hepato-biliary disorders: Skin and subcutaneous tissue disorders: Musculoskeletal and connective tissue disorders: Renal and urinary disorders: Reproductive system and breast disorders: General disorders and administration site conditions: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Hypertriglyceridemia, hypokalemia Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness Visual disturbances, including vision blurred and diplopia Transient or permanent hearing loss, tinnitus Congestive heart failure Pulmonary edema, dyspnea Pancreatitis, abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, pruritus Myalgia, arthralgia Urinary incontinence, pollakiuria Menstrual disorders, erectile dysfunction Peripheral edema, pyrexia There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX® has not been established. Reference ID: 3118502 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.) OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX® (itraconazole) Oral Solution or up to 3000 mg of SPORANOX® (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses. DOSAGE AND ADMINISTRATION SPORANOX® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX® Capsules is a different preparation than SPORANOX® Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used. Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX® Capsules and SPORANOX® Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. 25 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX®. Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS for further information.) Use in Patients with Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.) HOW SUPPLIED SPORANOX® (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 × 10 capsules (NDC 50458-290 01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs × 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children. © Ortho-McNeil-Janssen Pharmaceuticals, Inc 2001 Revised April 2012 Capsule contents manufactured by: Janssen Pharmaceutica N.V. Olen, Belgium Manufactured by: 26 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda JOLLC, Gurabo, Puerto Rico 00778 Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 27 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION 100 mg SPORANOX® (itraconazole) Capsules This summary contains important information about SPORANOX® (SPOR-ah-nox). This information is for patients who have been prescribed SPORANOX® to treat fungal nail infections. If your doctor prescribed SPORANOX® for medical problems other than fungal nail infections, ask your doctor if there is any information in this summary that does not apply to you. Read this information carefully each time you start to use SPORANOX®. This information does not take the place of discussion between you and your doctor. Only your doctor can decide if SPORANOX® is the right treatment for you. If you do not understand some of this information or have any questions, talk with your doctor or pharmacist. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT SPORANOX®? SPORANOX® is used to treat fungal nail infections. However, SPORANOX® is not for everyone. Do not take SPORANOX® for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take SPORANOX® if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See “Who Should Not Take SPORANOX®?” below.) If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is safe for you to take SPORANOX®. WHAT HAPPENS IF I HAVE A FUNGAL NAIL INFECTION? Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort. WHAT IS SPORANOX®? SPORANOX® is a prescription medicine used to treat fungal infections of the toenails and fingernails. It is also used to treat some types of fungal infections in other areas of your body. We do not know if SPORANOX® works in children with fungal nail infections or if it is safe for children to take. 28 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX® comes in the form of capsules and liquid (oral solution). The capsule and liquid forms work differently, so you should not use one in place of the other. This Patient Information discusses only the capsule form of SPORANOX®. You will get these capsules in a medicine bottle or a SPORANOX PulsePak®. The PulsePak® contains 28 capsules for treatment of your fungal nail infection. SPORANOX® goes into your bloodstream and travels to the source of the infection underneath the nail so that it can fight the infection there. Improved nails may not be obvious for several months after the treatment period is finished because it usually takes about 6 months to grow a new fingernail and 12 months to grow a new toenail. WHO SHOULD NOT TAKE SPORANOX®? SPORANOX® is not for everyone. Your doctor will decide if SPORANOX® is the right treatment for you. Some patients should not take SPORANOX® because they may have certain health problems or may be taking certain medicines that could lead to serious or life-threatening medical problems. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking, including dietary supplements and herbal remedies. Also tell your doctor about any other medical conditions you have had, especially heart, lung, liver or kidney conditions. Never take SPORANOX® if you:  have had heart failure, including congestive heart failure.  are taking any of the medicines listed below. Dangerous or even life-threatening abnormal heartbeats could result:  quinidine (such as Cardioquin®, Quinaglute®, Quinidex®)  dofetilide (such as Tikosyn™)  cisapride (such as Propulsid®)  pimozide (such as Orap®)  methadone (such as Dolophine®)  levacetylmethadol (such as Orlaam®)  are taking any of the following medicines:  lovastatin (such as Mevacor®, Advicor®, Altocor™)  simvastatin (such as Zocor®)  triazolam (such as Halcion®) 29 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  midazolam (such as Versed®)  nisoldipine (such as Sular®)  felodipine (such as Plendil®)  ergot alkaloids (such as Migranal®, Ergonovine, Cafergot®, Methergine®)  have ever had an allergic reaction to itraconazole or any of the other ingredients in SPORANOX® Capsules. Ask your doctor or pharmacist for a list of these ingredients. Taking SPORANOX® with certain other medicines could lead to serious or life-threatening medical problems. For example, taking fentanyl, a strong opioid narcotic pain medicine, with SPORANOX® could cause serious side effects, including trouble breathing, that may be life- threatening. Tell your doctor and pharmacist the name of all the prescription and non prescription medicines you are taking. Your doctor will decide if SPORANOX® is the right treatment for you. WHAT SHOULD I KNOW ABOUT SPORANOX® AND PREGNANCY OR BREAST FEEDING? Never take SPORANOX® if you have a fungal nail infection and are pregnant or planning to become pregnant within 2 months after you have finished your treatment. If you are able to become pregnant, you should use effective birth control during SPORANOX® treatment and for 2 months after finishing treatment. Ask your doctor about effective types of birth control. If you are breast-feeding, talk with your doctor about whether you should take SPORANOX®. HOW SHOULD I TAKE SPORANOX®? Always take SPORANOX® Capsules during or right after a full meal. Your doctor will decide the right dose for you. Depending on your infection, you will take SPORANOX® once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing schedule. You will receive either a bottle of capsules or a PulsePak®. Do not skip any doses. Be sure to finish all your SPORANOX® as prescribed by your doctor. If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven’t had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking SPORANOX® can develop liver problems. If you forget to take or miss doses of SPORANOX®, ask your doctor what you should do with the missed doses. 30 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda THE SPORANOX PULSEPAK® If you use the PulsePak®, you will take SPORANOX® for 1 week and then take no SPORANOX® for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The SPORANOX PulsePak® contains enough medicine for one “pulse” (1 week of treatment). The SPORANOX PulsePak® comes with special instructions. It contains 7 pouches-one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of the card, fold it back along the dashed line and peel away the backing so that you can remove 2 capsules.  Take 2 capsules in the morning and 2 capsules in the evening. This means you will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all of the capsules in the PulsePak® box.  After you finish the PulsePak®, do not take any SPORANOX® for the next 3 weeks. Even though you are not taking any capsules during this time, SPORANOX® keeps working inside your nails to help fight the fungal infection.  You will need more than one “pulse” to treat your fungal nail infection. When your doctor prescribes another pulse treatment, be sure to get your refill before the end of week 4. SPORANOX® Pulse Dosing Take 2 SPORANOX® capsules twice a day for 1 week Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 AM PM AM PM AM PM AM PM AM PM AM PM AM PM Week 1 // // // // // // // // // // // // // // Week 2 For the next 3 weeks, do not take any SPORANOX® capsules. Remember to get a refill before the end of Week 4 when your doctor prescribes another PulsePak® . Week 3 Week 4 WHAT ARE THE POSSIBLE SIDE EFFECTS OF SPORANOX®? The most common side effects that cause people to stop treatment either for a short time or completely include: skin rash, high triglyceride test results, high liver test results, and digestive system problems (such as nausea, bloating, and diarrhea). Stop SPORANOX® and call your doctor or get medical assistance right away if you have a severe allergic reaction. Symptoms of an allergic reaction may include skin rash, itching, hives, 31 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda shortness of breath or difficulty breathing, and/or swelling of the face. Very rarely, an oversensitivity to sunlight, a tingling sensation in the limbs or a severe skin disorder can occur. If any of these symptoms occur, stop taking SPORANOX® and contact your doctor. Stop SPORANOX® and call your doctor right away if you develop shortness of breath; have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up white or pink phlegm; have unusual fast heartbeats; or begin to wake up at night. In rare cases, patients taking SPORANOX® could develop serious heart problems, and these could be warning signs of heart failure. Stop SPORANOX® and call your doctor right away if you become unusually tired; lose your appetite; or develop nausea, abdominal pain, or vomiting, a yellow color to your skin or eyes, or dark colored urine or pale stools (bowel movements). In rare cases, patients taking SPORANOX® could develop serious liver problems and these could be warning signs. Stop SPORANOX® and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking SPORANOX® have reported temporary or permanent hearing loss. Call your doctor right away if you develop tingling or numbness in your extremities (hands or feet), if your vision gets blurry or you see double, if you hear a ringing in your ears, if you lose the ability to control your urine or urinate much more than usual. Additional possible side effects include upset stomach, vomiting, abdominal pain, constipation, headache, fever, inflammation of the pancreas, menstrual disorders, erectile dysfunction, dizziness, muscle weakness or pain, painful joints, unpleasant taste, or hair loss. These are not all the side effects of SPORANOX®. Your doctor or pharmacist can give you a more complete list. WHAT SHOULD I DO IF I TAKE AN OVERDOSE OF SPORANOX®? If you think you took too much SPORANOX®, call your doctor or local poison control center, or go to the nearest hospital emergency room right away. HOW SHOULD I STORE SPORANOX®? Keep all medicines, including SPORANOX®, out of the reach of children. Store SPORANOX® Capsules and the PulsePak® at room temperature in a dry place away from light. 32 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda GENERAL ADVICE ABOUT SPORANOX® Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use SPORANOX® for a condition for which it was not prescribed. Do not give SPORANOX® to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about SPORANOX®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about SPORANOX® that is written for health professionals or you can call 1-800 526-7736. This patient information has been approved by the U.S. Food and Drug Administration. The following are registered trademarks of their respective manufacturers: Mevacor® (Merck & Co., Inc.), Advicor® (Kos Pharmaceuticals, Inc.), Altocor™ (Andrx Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid® (Janssen Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis Pharmaceuticals Corporation), Methergine® (Novartis Pharmaceuticals Corporation), Orap® (Gate Pharmaceuticals), Sular® (Sciele Pharma, Inc.), Dolophine® (PD-Rx Pharmaceuticals, Inc), and Plendil® (AstraZeneca LP). Corporate Logo © Ortho-McNeil-Janssen Pharmaceuticals, Inc 2001 Printed in USA/ Revised: April 2012 33 Reference ID: 3118502 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:42.628481	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020083s048s049s050lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 50}
12,199	NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 3 PRODUCT INFORMATION ZOVIRAX® (acyclovir) Capsules ZOVIRAX® (acyclovir) Tablets ZOVIRAX® (acyclovir) Suspension DESCRIPTION: ZOVIRAX is the brand name for acyclovir, a synthetic nucleoside analogue active against herpesviruses. ZOVIRAX Capsules, Tablets, and Suspension are formulations for oral administration. Each capsule of ZOVIRAX contains 200 mg of acyclovir and the inactive ingredients corn starch, lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C Blue No. 2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink. Each 800-mg tablet of ZOVIRAX contains 800 mg of acyclovir and the inactive ingredients FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Each 400-mg tablet of ZOVIRAX contains 400 mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Each teaspoonful (5 mL) of ZOVIRAX Suspension contains 200 mg of acyclovir and the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as preservatives), carboxymethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol. Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H- purin-6-one; it has the following structural formula: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 4 VIROLOGY: Mechanism of Antiviral Action: Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK. Antiviral Activities: The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL. Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 5 poor clinical response during therapy. CLINICAL PHARMACOLOGY: Pharmacokinetics: The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in Table 1. Table 1: Acyclovir Pharmacokinetic Characteristics (Range) Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 h Average oral bioavailability 10% to 20%* *Bioavailability decreases with increasing dose. In one multiple-dose, cross-over study in healthy subjects (n = 23), it was shown that increases in plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in Table 2. The decrease in bioavailability is a function of the dose and not the dosage form. Table 2: Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg max SS C 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL trough SS C 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL There was no effect of food on the absorption of acyclovir (n = 6); therefore, ZOVIRAX Capsules, Tablets, and Suspension may be administered with or without food. The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 6 Special Populations: Adults with Impaired Renal Function: The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION). Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use). Pediatrics: In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m2 and 600 mg/m2 in pediatric patients ages 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours). Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. Clinical Trials: Initial Genital Herpes: Double-blind, placebo-controlled studies have demonstrated that orally administered ZOVIRAX significantly reduced the duration of acute infection and duration of lesion healing. The duration of pain and new lesion formation was decreased in some patient groups. Recurrent Genital Herpes: Double-blind, placebo-controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered ZOVIRAX given daily for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients. In a study of patients who received ZOVIRAX 400 mg twice daily for 3 years, 45%, 52%, and 63% of patients remained free of recurrences in the first, second, and third years, respectively. Serial analyses of the 3-month recurrence rates for the patients showed that 71% to 87% were recurrence free in each quarter. Herpes Zoster Infections: In a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, ZOVIRAX (800 mg 5 times daily for 10 days) shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the duration of viral shedding and the duration of new lesion formation. In a similar double-blind, placebo-controlled study, ZOVIRAX (800 mg 5 times daily for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 7 7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain, reduced the duration of new lesion formation, and reduced the prevalence of localized zoster-associated neurologic symptoms (paresthesia, dysesthesia, or hyperesthesia). Treatment was begun within 72 hours of rash onset and was most effective if started within the first 48 hours. Adults greater than 50 years of age showed greater benefit. Chickenpox: Three randomized, double-blind, placebo-controlled trials were conducted in 993 pediatric patients ages 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In 2 trials, ZOVIRAX was administered at 20 mg/kg 4 times daily (up to 3200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 days. Treatment with ZOVIRAX shortened the time to 50% healing, reduced the maximum number of lesions, reduced the median number of vesicles, decreased the median number of residual lesions on day 28, and decreased the proportion of patients with fever, anorexia, and lethargy by day 2. Treatment with ZOVIRAX did not affect varicella-zoster virus-specific humoral or cellular immune responses at 1 month or 1 year following treatment. INDICATIONS AND USAGE: Herpes Zoster Infections: ZOVIRAX is indicated for the acute treatment of herpes zoster (shingles). Genital Herpes: ZOVIRAX is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes. Chickenpox: ZOVIRAX is indicated for the treatment of chickenpox (varicella). CONTRAINDICATIONS: ZOVIRAX is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir. WARNINGS: ZOVIRAX Capsules, Tablets, and Suspension are intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 8 Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy. PRECAUTIONS: Dosage adjustment is recommended when administering ZOVIRAX to patients with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also be exercised when administering ZOVIRAX to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with intravenous acyclovir. Information for Patients: Patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered ZOVIRAX, or they have any other questions. Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. Genital Herpes Infections: Patients should be informed that ZOVIRAX is not a cure for genital herpes. There are no data evaluating whether ZOVIRAX will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode. Chickenpox: Chickenpox in otherwise healthy children is usually a self-limited disease of mild to moderate severity. Adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course. Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics. Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 9 800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors. Maximum plasma concentrations were 3 to 6 times human levels in the mouse bioassay and 1 to 2 times human levels in the rat bioassay. Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclvoir was positive in 5 of the assays. Acyclovir did not impair fertility or reproduction in mice (450 mg/kg per day, PO) or in rats (25 mg/kg per day, SC). In the mouse study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg per day, SC) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg per day, SC, there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses. No testicular abnormalities were seen in dogs given 50 mg/kg per day, IV for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg per day orally for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels. Pregnancy: Teratogenic Effects: Pregnancy Category B. Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per day, SC and IV), or rat (50 mg/kg per day, SC). These exposures resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels. There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 10 defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of ZOVIRAX and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. ZOVIRAX should be administered to a nursing mother with caution and only when indicated. Pediatric Use: Safety and effectiveness of oral formulations of acyclovir in pediatric patients less than 2 years of age have not been established. Geriatric Use: Of 376 subjects who received ZOVIRAX in a clinical study of herpes zoster treatment in immunocompetent subjects greater than or equal to 50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects. The duration of pain after healing was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS: Herpes Simplex: Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with ZOVIRAX 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 11 Long-Term Administration: The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times daily for 1 year in 586 patients treated with ZOVIRAX were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with ZOVIRAX for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%). Herpes Zoster: The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral ZOVIRAX 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%). Chickenpox: The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral ZOVIRAX at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%). Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of ZOVIRAX. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to ZOVIRAX, or a combination of these factors. General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema. Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see PRECAUTIONS). Digestive: Diarrhea, gastrointestinal distress, nausea. Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia. Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal: Myalgia. Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 12 Special Senses: Visual abnormalities. Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS). OVERDOSAGE: Overdoses involving ingestion of up to 100 capsules (20 g) have been reported. Adverse events that have been reported in association with overdosage include agitation, coma, convulsions, and lethargy. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Overdosage has been reported following bolus injections or inappropriately high doses and in patients whose fluid and electrolyte balance were not properly monitored. This has resulted in elevated BUN and serum creatinine and subsequent renal failure. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION). DOSAGE AND ADMINISTRATION: Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days. Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily. The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re-evaluated to assess the need for continuation of therapy with ZOVIRAX. Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence. Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg per day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox. Adults and Children over 40 kg: 800 mg 4 times daily for 5 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 13 Intravenous ZOVIRAX is indicated for the treatment of varicella-zoster infections in immunocompromised patients. When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms. Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of ZOVIRAX Capsules, Tablets, or Suspension should be modified as shown in Table 3: Table 3: Dosage Modification for Renal Impairment Creatinine Adjusted Dosage Regimen Normal Dosage Regimen Clearance (mL/min/1.73 m2) Dose (mg) Dosing Interval >10 200 every 4 hours, 5x daily 200 mg every 4 hours 0-10 200 every 12 hours 400 mg every 12 hours >10 0-10 400 200 every 12 hours every 12 hours >25 800 every 4 hours, 5x daily 800 mg every 4 hours 10-25 800 every 8 hours 0-10 800 every 12 hours Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis. Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the dosing interval. Bioequivalence of Dosage Forms: ZOVIRAX Suspension was shown to be bioequivalent to ZOVIRAX Capsules (n = 20) and 1 ZOVIRAX 800-mg tablet was shown to be bioequivalent to 4 ZOVIRAX 200-mg capsules (n = 24). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/S-026, S-027 NDA 19-909/S-016, S-017 NDA 20-089/S-015, S-016 Page 14 HOW SUPPLIED: ZOVIRAX Capsules (blue, opaque cap and body) containing 200 mg acyclovir and printed with “Wellcome ZOVIRAX 200” – Bottle of 100 (NDC 0173-0991-55) and unit dose pack of 100 (NDC 0173-0991-56). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Tablets (light blue, oval) containing 800 mg acyclovir and engraved with “ZOVIRAX 800” – Bottle of 100 (NDC 0173-0945-55) and unit dose pack of 100 (NDC 0173- 0945-56). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Tablets (white, shield-shaped) containing 400 mg acyclovir and engraved with "ZOVIRAX" on one side and a triangle on the other side – Bottle of 100 (NDC 0173-0949-55). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Suspension (off-white, banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL) (NDC 0173-0953-96). Store at 15° to 25°C (59° to 77°F). GlaxoSmithKline Research Triangle Park, NC 27709 2001, GlaxoSmithKline All rights reserved. Date of Issue RL-no. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Debra Birnkrant 11/14/01 01:57:54 PM NDA 19-909 SLR 017, 016 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:42.710198	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20089s15s16lbl.pdf', 'application_number': 20089, 'submission_type': 'SUPPL ', 'submission_number': 16}
12,200	NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 3 PRESCRIBING INFORMATION ZOVIRAX® (acyclovir) Capsules ZOVIRAX® (acyclovir) Tablets ZOVIRAX® (acyclovir) Suspension DESCRIPTION ZOVIRAX is the brand name for acyclovir, a synthetic nucleoside analogue active against herpesviruses. ZOVIRAX Capsules, Tablets, and Suspension are formulations for oral administration. Each capsule of ZOVIRAX contains 200 mg of acyclovir and the inactive ingredients corn starch, lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C Blue No. 2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink. Each 800-mg tablet of ZOVIRAX contains 800 mg of acyclovir and the inactive ingredients FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Each 400-mg tablet of ZOVIRAX contains 400 mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Each teaspoonful (5 mL) of ZOVIRAX Suspension contains 200 mg of acyclovir and the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as preservatives), carboxymethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol. Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6- one; it has the following structural formula: VIROLOGY This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 4 Mechanism of Antiviral Action: Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK. Antiviral Activities: The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL. Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy. CLINICAL PHARMACOLOGY Pharmacokinetics: The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in Table 1. Table 1. Acyclovir Pharmacokinetic Characteristics (Range) Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 hr Average oral bioavailability 10% to 20%* *Bioavailability decreases with increasing dose. In one multiple-dose, crossover study in healthy subjects (n = 23), it was shown that increases in plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in Table 2. The decrease in bioavailability is a function of the dose and not the dosage form. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 5 Table 2. Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg max SS C 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL trough SS C 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL There was no effect of food on the absorption of acyclovir (n = 6); therefore, ZOVIRAX Capsules, Tablets, and Suspension may be administered with or without food. The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine. Special Populations: Adults with Impaired Renal Function: The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION). Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use). Pediatrics: In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m2 and 600 mg/m2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours). Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. Clinical Trials: Initial Genital Herpes: Double-blind, placebo-controlled studies have demonstrated that orally administered ZOVIRAX significantly reduced the duration of acute infection and duration of lesion healing. The duration of pain and new lesion formation was decreased in some patient groups. Recurrent Genital Herpes: Double-blind, placebo-controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered ZOVIRAX given daily for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients. In a study of patients who received ZOVIRAX 400 mg twice daily for 3 years, 45%, 52%, and 63% of patients remained free of recurrences in the first, second, and third years, respectively. Serial analyses of the 3-month recurrence rates for the patients showed that 71% to 87% were recurrence free in each quarter. Herpes Zoster Infections: In a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, ZOVIRAX (800 mg 5 times daily for 10 days) shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the duration of viral shedding and the duration of new lesion formation. In a similar double-blind, placebo-controlled study, ZOVIRAX (800 mg 5 times daily for 7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain; reduced the duration of new lesion formation; and reduced the prevalence of localized zoster-associated neurologic symptoms (paresthesia, dysesthesia, or hyperesthesia). Treatment was begun within 72 hours of rash onset and was most effective if started within the first 48 hours. Adults greater than 50 years of age showed greater benefit. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 6 Chickenpox: Three randomized, double-blind, placebo-controlled trials were conducted in 993 pediatric patients aged 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In 2 trials, ZOVIRAX was administered at 20 mg/kg 4 times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 days. Treatment with ZOVIRAX shortened the time to 50% healing; reduced the maximum number of lesions; reduced the median number of vesicles; decreased the median number of residual lesions on day 28; and decreased the proportion of patients with fever, anorexia, and lethargy by day 2. Treatment with ZOVIRAX did not affect varicella-zoster virus-specific humoral or cellular immune responses at 1 month or 1 year following treatment. INDICATIONS AND USAGE Herpes Zoster Infections: ZOVIRAX is indicated for the acute treatment of herpes zoster (shingles). Genital Herpes: ZOVIRAX is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes. Chickenpox: ZOVIRAX is indicated for the treatment of chickenpox (varicella). CONTRAINDICATIONS ZOVIRAX is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir. WARNINGS ZOVIRAX Capsules, Tablets, and Suspension are intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE). Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy. PRECAUTIONS Dosage adjustment is recommended when administering ZOVIRAX to patients with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also be exercised when administering ZOVIRAX to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with intravenous acyclovir. Information for Patients: Patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered ZOVIRAX, or they have any other questions. Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. Genital Herpes Infections: Patients should be informed that ZOVIRAX is not a cure for genital herpes. There are no data evaluating whether ZOVIRAX will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 7 Chickenpox: Chickenpox in otherwise healthy children is usually a self-limited disease of mild to moderate severity. Adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course. Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics. Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors. Maximum plasma concentrations were 3 to 6 times human levels in the mouse bioassay and 1 to 2 times human levels in the rat bioassay. Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 5 of the assays. Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats (25 mg/kg/day, s.c.). In the mouse study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg/day, s.c., there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses. No testicular abnormalities were seen in dogs given 50 mg/kg/day, IV for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels. Pregnancy: Teratogenic Effects: Pregnancy Category B. Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, s.c. and IV), or rat (50 mg/kg/day, s.c.). These exposures resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels. There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of ZOVIRAX and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. ZOVIRAX should be administered to a nursing mother with caution and only when indicated. Pediatric Use: Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 8 Geriatric Use: Of 376 subjects who received ZOVIRAX in a clinical study of herpes zoster treatment in immunocompetent subjects ≥50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects. The duration of pain after healing was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Herpes Simplex: Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with ZOVIRAX 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo. Long-Term Administration: The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times daily for 1 year in 586 patients treated with ZOVIRAX were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with ZOVIRAX for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%). Herpes Zoster: The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral ZOVIRAX 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%). Chickenpox: The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral ZOVIRAX at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%). Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of ZOVIRAX. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to ZOVIRAX, or a combination of these factors. General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema. Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see PRECAUTIONS). Digestive: Diarrhea, gastrointestinal distress, nausea. Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia. Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal: Myalgia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 9 Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria. Special Senses: Visual abnormalities. Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS). OVERDOSAGE Overdoses involving ingestion of up to 100 capsules (20 g) have been reported. Adverse events that have been reported in association with overdosage include agitation, coma, seizures, and lethargy. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Overdosage has been reported following bolus injections or inappropriately high doses and in patients whose fluid and electrolyte balance were not properly monitored. This has resulted in elevated BUN and serum creatinine and subsequent renal failure. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION). DOSAGE AND ADMINISTRATION Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days. Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily. The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re- evaluated to assess the need for continuation of therapy with ZOVIRAX. Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence. Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox. Adults and Children over 40 kg: 800 mg 4 times daily for 5 days. Intravenous ZOVIRAX is indicated for the treatment of varicella-zoster infections in immunocompromised patients. When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms. Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of ZOVIRAX Capsules, Tablets, or Suspension should be modified as shown in Table 3: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 10 Table 3. Dosage Modification for Renal Impairment Creatinine Adjusted Dosage Regimen Normal Dosage Regimen Clearance (mL/min/1.73 m2) Dose (mg) Dosing Interval 200 mg every 4 hours >10 200 every 4 hours, 5x daily 0-10 200 every 12 hours 400 mg every 12 hours >10 0-10 400 200 every 12 hours every 12 hours 800 mg every 4 hours >25 800 every 4 hours, 5x daily 10-25 800 every 8 hours 0-10 800 every 12 hours Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis. Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the dosing interval. Bioequivalence of Dosage Forms: ZOVIRAX Suspension was shown to be bioequivalent to ZOVIRAX Capsules (n = 20) and 1 ZOVIRAX 800-mg tablet was shown to be bioequivalent to 4 ZOVIRAX 200-mg capsules (n = 24). HOW SUPPLIED ZOVIRAX Capsules (blue, opaque cap and body) containing 200 mg acyclovir and printed with “Wellcome ZOVIRAX 200.” Bottle of 100 (NDC 0173-0991-55). Unit dose pack of 100 (NDC 0173-0991-56). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Tablets (light blue, oval) containing 800 mg acyclovir and engraved with “ZOVIRAX 800.” Bottle of 100 (NDC 0173-0945-55). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Tablets (white, shield-shaped) containing 400 mg acyclovir and engraved with "ZOVIRAX" on one side and a triangle on the other side. Bottle of 100 (NDC 0173-0949-55). Store at 15° to 25°C (59° to 77°F) and protect from moisture. ZOVIRAX Suspension (off-white, banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL). Bottle of 1 pint (473 mL) (NDC 0173-0953-96). Store at 15° to 25°C (59° to 77°F). GlaxoSmithKline This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18-828/SLR-029 NDA 19-909/SLR-019 NDA 20-089/SLR-018 Page 11 Research Triangle Park, NC 27709 2003, GlaxoSmithKline. All rights reserved. November 2003 RL-2049 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:42.812966	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18828slr029,19909slr019,20089slr018_zovirax_lbl.pdf', 'application_number': 20089, 'submission_type': 'SUPPL ', 'submission_number': 18}
12,201	DIFLUCAN® (Fluconazole Tablets) (Fluconazole Injection - for intravenous infusion only) (Fluconazole for Oral Suspension) DESCRIPTION DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight 306.3. The structural formula is: CH2 CH2 C N N N N N N OH F F Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in Viaflex® Plus plastic containers. The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Mode of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 alpha-demethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Pharmacokinetics and Metabolism The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL). Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Ratio of Fluconazole Tissue (Fluid)/Plasma Tissue or Fluid Concentration* Cerebrospinal fluid† 0.5-0.9 Saliva 1 Sputum 1 Blister fluid 1 Urine 10 Normal skin 10 Nails 1 Blister skin 2 Vaginal tissue 1 Vaginal fluid 0.4-0.7 * Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics in Children In children, the following pharmacokinetic data {Mean(%cv)} have been reported: Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) Cmax (µg/mL) Vdss (L/kg) 9 Months- 13 years Single-Oral 2 mg/kg 0.40 (38%) N=14 25.0 2.9 (22%) N=16 ___ 9 Months- 13 years Single-Oral 8 mg/kg 0.51 (60%) N=15 19.5 9.8 (20%) N=15 ___ 5-15 years Multiple IV 2 mg/kg 0.49 (40%) N=4 17.4 5.5 (25%) N=5 0.722 (36%) N=4 5-15 years Multiple IV 4 mg/kg 0.59 (64%) N=5 15.2 11.4 (44%) N=6 0.729 (33%) N=5 5-15 years Multiple IV 8 mg/kg 0.66 (31%) N=7 17.6 14.1 (22%) N=8 1.069 (37%) N=7 Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later. Pharmacokinetics in Elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4+ 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject’s terminal elimination half-life versus creatinine clearance compared with the predicted half-life – creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life – creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly. Drug Interaction Studies Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18-31%) and 13% (95% C.I. range 8-18%), respectively relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC individual values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment. Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased 19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers. Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of fluconazole. Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31% (range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10 to –50%). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.) Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response. Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.) Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased 60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.) Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2. Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17% (range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See PRECAUTIONS.) Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400-mg and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.) Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily for 7 days. In these three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of placebo treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS.) Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.) Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean ± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.) Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean ± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19% (range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS.) Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See PRECAUTIONS.) Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.) Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.) Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.) Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Microbiology Fluconazole exhibits in vitro activity against Cryptococcus neoformans and Candida spp. Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown. Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis. Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cr. neoformans, and antagonism of the two drugs in systemic infection with Asp. fumigatus. The clinical significance of results obtained in these studies is unknown. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. INDICATIONS AND USAGE DIFLUCAN (fluconazole) is indicated for the treatment of: 1. Vaginal candidiasis (vaginal yeast infections due to Candida). 2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL STUDIES Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.) Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation. The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group. Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days Enrolled 448 422 Evaluable at Late Follow-up 347 (77%) 327 (77%) Clinical cure 239/347 (69%) 235/327 (72%) Mycologic erad. 213/347 (61%) 196/327 (60%) Therapeutic cure 190/347 (55%) 179/327 (55%) Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication and 59% therapeutic cure when treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parameter Fluconazole PO Vaginal Products Evaluable patients 448 422 With any adverse event 141 (31%) 112 (27%) Nervous System 90 (20%) 69 (16%) Gastrointestinal 73 (16%) 18 ( 4%) With drug-related event 117 (26%) 67 (16%) Nervous System 61 (14%) 29 ( 7%) Headache 58 (13%) 28 ( 7%) Gastrointestinal 68 (15%) 13 ( 3%) Abdominal pain 25 ( 6%) 7 ( 2%) Nausea 30 ( 7%) 3 ( 1%) Diarrhea 12 ( 3%) 2 (<1%) Application site event 0 ( 0%) 19 ( 5%) Taste Perversion 6 ( 1%) 0 ( 0%) Pediatric Studies Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole. Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients. Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication* 55/72 (76%) 6/54 (11%) * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response. The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23% for nystatin. CONTRAINDICATIONS DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of cisapride is This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda contraindicated in patients receiving DIFLUCAN (fluconazole). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.) WARNINGS (1) Hepatic injury: DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress. PRECAUTIONS General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Single Dose The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) Clinically or potentially significant drug interactions between This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Tacrolimus Short-acting benzodiazepines Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200-mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400-mg and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Cisapride: There have been reports of cardiac events, including torsade de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval.The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Astemizole: The use of fluconazole in patients concurrently taking astemizole or other drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when coadministering fluconazole. Patients should be carefully monitored. Rifabutin: There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus: There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-containing oral contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels; however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and levonorgestrel levels. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The data presently available indicate that the decreases in some individual ethinyl estradiol and levonorgestrel AUC values with fluconazole treatment are likely the result of random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or levonorgestrel metabolism. The clinical significance of these effects is presently unknown. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur. Carcinogenesis, Mutagenesis and Impairment of Fertility Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 µg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.) Pregnancy Teratogenic Effects. Pregnancy Category C: Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies, at 5, 10 and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were detected. In several studies in which pregnant rats were treated orally with fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis and parturition. There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis (an unindicated use). The relationship between fluconazole use and these events is unclear. DIFLUCAN should be used in pregnancy only if the potential benefit justifies the possible risk to the fetus. Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of DIFLUCAN in nursing mothers is not recommended. Pediatric Use An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.) The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.) Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN. Geriatric Use In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during post-marketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.) Central Nervous System: Seizures, dizziness. Dermatologic: Exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS), alopecia. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Dyspepsia, vomiting. Other Senses: Taste perversion. Adverse Reactions in Children: In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 OVERDOSAGE There have been reports of overdosage with DIFLUCAN (fluconazole). A 42-year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behavior after reportedly ingesting 8200 mg of DIFLUCAN. The patient was admitted to the hospital, and his condition resolved within 48 hours. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%. In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions. DOSAGE AND ADMINISTRATION Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended DIFLUCAN daily dosage for the prevention of candidiasis of patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children: The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12* mg/kg 400 mg * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140-age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for intravenous administration using sterile equipment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. DO NOT ADD SUPPLEMENTARY MEDICATION. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Preparation for Administration: 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. HOW SUPPLIED DIFLUCAN® Tablets: Pink trapezoidal tablets containing 50, 100 or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN® Tablets are supplied as follows: DIFLUCAN® 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG” on the back. NDC 0049-3410-30 Bottles of 30 DIFLUCAN® 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and “ROERIG” on the back. NDC 0049-3420-30 Bottles of 30 NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN® 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and “ROERIG” on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN® 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and “ROERIG” on the back. NDC 0049-3430-30 Bottles of 30 NDC 0049-3430-41 Unit dose package of 100 Storage: Store tablets below 86°F (30°C). DIFLUCAN® for Oral Suspension: DIFLUCAN® for oral suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottle NDC 0049-3450-19 Fluconazole 1400 mg per bottle Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN® Injections: DIFLUCAN® injections for intravenous infusion administration are formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or 200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN® injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose diluents. DIFLUCAN® Injections in Glass Bottles: NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing. DIFLUCAN® Injections in Viaflex® Plus Plastic Containers: NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6 NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6 Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does not adversely affect the product. Protect from freezing.Rx only  2004 PFIZER INC LAB-0099 –6.1 Revised August2004 Roerig Division of Pfizer Inc, NY, NY 10017 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:42.886910	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19949s30,32,35,19950s31,33,37,20090s12,14,17lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 12}
12,203	1 23-4526-00-1 PATIENT INFORMATION DIFLUCAN (fluconazole tablets) This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not meant to take the place of your doctor's instructions. Read this information carefully before you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about DIFLUCAN. What Is DIFLUCAN? DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the yeast infection goes away. DIFLUCAN is different from other treatments for vaginal yeast infections because it is a tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet is only about using DIFLUCAN for vaginal yeast infections. For information about using DIFLUCAN for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information about vaginal yeast infections. What Is A Vaginal Yeast Infection? It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are common. About three out of every four adult women will have at least one vaginal yeast infection during their life. Some medicines and medical conditions can increase your chance of getting a yeast infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast infections more often than other women. Personal hygiene and certain types of clothing may increase your chances of getting a yeast infection. Ask your doctor for tips on what you can do to help prevent vaginal yeast infections. If you get a vaginal yeast infection, you may have any of the following symptoms: • itching • a burning feeling when you urinate • redness • soreness • a thick white vaginal discharge that looks like cottage cheese This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 What To Tell Your Doctor Before You Start DIFLUCAN? Do not take Diflucan if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including: • diabetes medicines you take by mouth such as glyburide, tolbutamide, glipizide • blood thinners such as warfarin • cyclosporine (used to prevent rejection of organ transplants) • rifampin or rifabutin (used for tuberculosis) • astemizole (used for allergies) • tacrolimus (used to prevent rejection of organ transplants) • phenytoin (used for seizures) • theophylline (used for asthma) • cisapride (Propulsid®; used for stomach acid problems) • terfenadine (Seldane®; used for allergies) Since there are many brand names for these medicines, check with your doctor or pharmacist if you have any questions. • are taking any over-the-counter medicines you can buy without a prescription, including natural or herbal remedies • have any liver problems. • have any other medical conditions • are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether DIFLUCAN is right for you. • are breast-feeding. DIFLUCAN can pass through breast milk to the baby. • are allergic to any other medicines including those used to treat yeast and other fungal infections. • are allergic to any of the ingredients in DIFLUCAN. The main ingredient of DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist. Who Should Not Take DIFLUCAN? To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking cisapride (Propulsid®) since it can cause changes in heartbeat in some people if taken with DIFLUCAN. How Should I Take DIFLUCAN Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time of the day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms start to go away after 24 hours. However, it may take several days for your symptoms to go away completely. If there is no change in your symptoms after a few days, call your doctor. [caption on the right of the illustration] Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection. What Should I Avoid While Taking DIFLUCAN? Some medicines can affect how well DIFLUCAN works. Check with your doctor before starting any new medicines within seven days of taking DIFLUCAN. What Are The Possible Side Effects of DIFLUCAN? Like all medicines, DIFLUCAN may cause some side effects that are usually mild to moderate. The most common side effects of DIFLUCAN are: • headache • diarrhea • nausea or upset stomach • dizziness • stomach pain • changes in the way food tastes Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs of an allergic reaction can include shortness of breath; coughing; wheezing; fever; chills; throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the body; or skin rash, hives, blisters or skin peeling. Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in patients with serious medical problems. Call your doctor if your skin or eyes become yellow, your urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit or feel like vomiting or if you have severe skin itching. In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin peeling have been reported. Tell your doctor right away if you get a rash while taking DIFLUCAN. DIFLUCAN may cause other less common side effects besides those listed here. If you develop any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor or pharmacist. What To Do For An Overdose This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 In case of an accidental overdose, call your doctor right away or go to the nearest emergency room. How To Store DIFLUCAN Keep DIFLUCAN and all medicines out of the reach of children. General Advice About Prescription Medicines Medicines are sometimes prescribed for conditions that are mentioned in patient information leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not give DIFLUCAN to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about DIFLUCAN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about DIFLUCAN that is written for health professionals. You can also visit the DIFLUCAN Internet site at www.diflucan.com. p U.S. Pharmaceuticals 2003, Pfizer Inc Revised June 2003 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:43.031390	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19949slr037,19950slr039,20090slr019_diflucan_lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 19}
12,202	1 PATIENT INFORMATION DIFLUCAN (fluconazole tablets) This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not meant to take the place of your doctor's instructions. Read this information carefully before you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about DIFLUCAN. What Is DIFLUCAN? DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the yeast infection goes away. DIFLUCAN is different from other treatments for vaginal yeast infections because it is a tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet is only about using DIFLUCAN for vaginal yeast infections. For information about using DIFLUCAN for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information about vaginal yeast infections. What Is A Vaginal Yeast Infection? It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are common. About three out of every four adult women will have at least one vaginal yeast infection during their life. Some medicines and medical conditions can increase your chance of getting a yeast infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast infections more often than other women. Personal hygiene and certain types of clothing may increase your chances of getting a yeast infection. Ask your doctor for tips on what you can do to help prevent vaginal yeast infections. If you get a vaginal yeast infection, you may have any of the following symptoms: • itching • a burning feeling when you urinate • redness • soreness • a thick white vaginal discharge that looks like cottage cheese This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 What To Tell Your Doctor Before You Start DIFLUCAN? Do not take Diflucan if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including: • diabetes medicines you take by mouth such as glyburide, tolbutamide, glipizide • blood thinners such as warfarin • cyclosporine (used to prevent rejection of organ transplants) • rifampin or rifabutin (used for tuberculosis) • astemizole (used for allergies) • tacrolimus (used to prevent rejection of organ transplants) • phenytoin (used for seizures) • theophylline (used for asthma) • cisapride (Propulsid®; used for stomach acid problems) Since there are many brand names for these medicines, check with your doctor or pharmacist if you have any questions. • are taking any over-the-counter medicines you can buy without a prescription, including natural or herbal remedies • have any liver problems. • have any other medical conditions • are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether DIFLUCAN is right for you. • are breast-feeding. DIFLUCAN can pass through breast milk to the baby. • are allergic to any other medicines including those used to treat yeast and other fungal infections. • are allergic to any of the ingredients in DIFLUCAN. The main ingredient of DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist. Who Should Not Take DIFLUCAN? To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking cisapride (Propulsid®) since it can cause changes in heartbeat in some people if taken with DIFLUCAN. How Should I Take DIFLUCAN This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time of the day. DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms start to go away after 24 hours. However, it may take several days for your symptoms to go away completely. If there is no change in your symptoms after a few days, call your doctor. [caption on the right of the illustration] Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection. What Should I Avoid While Taking DIFLUCAN? Some medicines can affect how well DIFLUCAN works. Check with your doctor before starting any new medicines within seven days of taking DIFLUCAN. What Are The Possible Side Effects of DIFLUCAN? Like all medicines, DIFLUCAN may cause some side effects that are usually mild to moderate. The most common side effects of DIFLUCAN are: • headache • diarrhea • nausea or upset stomach • dizziness • stomach pain • changes in the way food tastes Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs of an allergic reaction can include shortness of breath; coughing; wheezing; fever; chills; throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the body; or skin rash, hives, blisters or skin peeling. Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in patients with serious medical problems. Call your doctor if your skin or eyes become yellow, your urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit or feel like vomiting or if you have severe skin itching. In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin peeling have been reported. Tell your doctor right away if you get a rash while taking DIFLUCAN. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 DIFLUCAN may cause other less common side effects besides those listed here. If you develop any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor or pharmacist. What To Do For An Overdose In case of an accidental overdose, call your doctor right away or go to the nearest emergency room. How To Store DIFLUCAN Keep DIFLUCAN and all medicines out of the reach of children. General Advice About Prescription Medicines Medicines are sometimes prescribed for conditions that are mentioned in patient information leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not give DIFLUCAN to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about DIFLUCAN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about DIFLUCAN that is written for health professionals. You can also visit the DIFLUCAN Internet site at www.diflucan.com. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Marc Cavaille Coll 8/7/02 04:23:43 PM Signing for Renata Albrecht This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:43.125494	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19949s33lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 15}
12,198	SPORANOX® (itraconazole) Capsules BOXED WARNING Congestive Heart Failure, Cardiac Effects and Drug Interactions: SPORANOX® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX® Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions: Coadministration of the following drugs are contraindicated with SPORANOX® Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. See CONTRAINDICATIONS and WARNINGS Sections, and PRECAUTIONS: Drug Interactions Section for specific examples. DESCRIPTION SPORANOX® is the brand name for itraconazole, an azole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one mixture with (±)-1-[(R)-sec-butyl]-4-[p-[4-[p-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H- 1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4- triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres (composed of sucrose, maize starch, and purified water). Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: General Pharmacokinetic Characteristics Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/ml, 1.1 μg/ml and 2.0 μg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Absorption Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%. The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (See PRECAUTIONS: Drug Interactions.) Absorption of itraconazole under fasted conditions in these subjects is increased when SPORANOX® Capsules are administered with an acidic beverage (such as a non-diet cola). When SPORANOX® Capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) Itraconazole exposure is lower with the Capsule formulation than with the Oral Solution when the same dose of drug is given. (see WARNINGS) Distribution Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (>700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma. Metabolism Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Excretion Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose. As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period. Special Populations: Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg oral dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20-49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar to that in healthy subjects (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy- itraconazole. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Hepatic Impairment: Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as capsule. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. (See CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX® Capsules, SPORANOX® should be discontinued. (See BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton species (see Description of Clinical Studies). Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Drug Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Cross-resistance: Several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV- infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Onychomycosis of the toenail: Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX® Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX® Capsules b.i.d., followed by a 3- week period without SPORANOX®, which was followed by a second 1-week pulse of 200 mg of SPORANOX® Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS Congestive Heart Failure: SPORANOX® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See BOXED WARNING, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations.) Drug Interactions: Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX®. Plasma concentrations increase for the following drugs: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pharmacologic effect and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Specific examples are listed in PRECAUTIONS: Drug Interactions. SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® is contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX® to patients with hypersensitivity to other azoles. WARNINGS Hepatic Effects: SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX® use or reinstitution of treatment with SPORANOX® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: SPORANOX® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX® therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX® Capsules, discontinue administration. Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. SPORANOX® has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and felodipine or nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post- marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Interaction potential: SPORANOX® has a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions. Interchangeability: SPORANOX® (itraconazole) Capsules and SPORANOX® Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. PRECAUTIONS General: SPORANOX® (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a non-diet cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with SPORANOX® treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving SPORANOX®. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Neuropathy: If neuropathy occurs that may be attributable to SPORANOX® Capsules, the treatment should be discontinued. Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Information for Patients: • The topical effects of mucosal exposure may be different between the SPORANOX® Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used interchangeably with SPORANOX® Oral Solution. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Instruct patients to take SPORANOX® Capsules with a full meal. SPORANOX® Capsules must be swallowed whole. • Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX® administration, they should discontinue SPORANOX® and contact their healthcare provider immediately. • Instruct patients to stop SPORANOX® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. • Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. • Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. • Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines. Drug Interactions: Itraconazole is mainly metabolized through CYP3A4. Other drugs that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other drugs that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages. Drugs that may decrease itraconazole plasma concentrations Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole capsules. It is recommended that these drugs be used with caution when coadministered with itraconazole capsules: • It is recommended that itraconazole capsules be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity. • It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of SPORANOX® Capsules. • Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Examples include: • Antibacterials: isoniazid, rifabutin (see also under ‘Drugs that may have their plasma concentrations increased by itraconazole’), rifampicin • Anticonvulsants: carbamazepine, (see also under ‘Drugs that may have their plasma concentrations increased by itraconazole’), phenobarbital, phenytoin • Antivirals: efavirenz, nevirapine Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary. Drugs that may increase itraconazole plasma concentrations Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include: • Antibacterials: ciprofloxacin, clarithromycin, erythromycin • Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under ‘Drugs that may have their plasma concentrations increased by itraconazole’), ritonavir (see also under ‘Drugs that may have their plasma concentrations increased by itraconazole’) It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary. Drugs that may have their plasma concentrations increased by itraconazole Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Once treatment is stopped, itraconazole plasma Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole: Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Drugs that may have their plasma concentrations increased by itraconazole Drug Class Contraindicated Not Recommended Use with Caution Comments Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole. It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. Alpha Blockers tamsulosin Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Drugs that may have their plasma concentrations increased by itraconazole Drug Class Contraindicated Not Recommended Use with Caution Comments Analgesics methadone alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil Methadone: The potential increase in plasma concentrations of methadone when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes. Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with SPORANOX® may increase the risk of potentially fatal respiratory depression. Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with SPORANOX®. Antiarrhythmics disopyramide, dofetilide, dronedarone, quinidine digoxin Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Drugs that may have their plasma concentrations increased by itraconazole Drug Class Contraindicated Not Recommended Use with Caution Comments Antibacterials rifabutin Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations’. Anticoagulants and Antiplatelet Drugs rivaroxaban coumarins, cilostazol, dabigatran Coumarins: SPORANOX® may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin. Anticonvulsants carbamazepine Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations’. Antidiabetics repaglinide, saxagliptin Antihelmintics and Antiprotozoals praziquantel Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Drugs that may have their plasma concentrations increased by itraconazole Drug Class Contraindicated Not Recommended Use with Caution Comments Antimigraine Drugs ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) eletriptan Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with SPORANOX® may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Antineoplastics irinotecan dasatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, ixabepilone, lapatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with SPORANOX® may increase the risk of potentially fatal adverse events. Antipsychotics, Anxiolytics and Hypnotics lurasidone, oral midazolam, pimozide, triazolam alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone Midazolam, triazolam: Coadministration of SPORANOX® and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Drugs that may have their plasma concentrations increased by itraconazole Drug Class Contraindicated Not Recommended Use with Caution Comments Antivirals maraviroc, indinavir, ritonavir saquinavir Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’. Beta Blockers nadolol Calcium Channel Blockers felodipine, nisoldipine other dihydropyridines, verapamil Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with SPORANOX® may increase the risk of congestive heart failure. Dihydropyridines: Concomitant administration of SPORANOX® may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving SPORANOX® and dihydropyridine calcium channel blockers. Cardiovascular Drugs, Miscellaneous ranolazine aliskiren Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Drugs that may have their plasma concentrations increased by itraconazole Drug Class Contraindicated Not Recommended Use with Caution Comments Diuretics eplerenone Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with SPORANOX® may increase the risk of hyperkalemia and hypotension. Gastrointestinal Drugs cisapride aprepitant Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation. Immunosuppressants everolimus, temsirolimus budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus Lipid Regulating Drugs lovastatin, simvastatin atorvastatin The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with SPORANOX® may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Respiratory Drugs salmeterol Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Drugs that may have their plasma concentrations increased by itraconazole Drug Class Contraindicated Not Recommended Use with Caution Comments Urological Drugs vardenafil fesoterodine. sildenafil, solifenacin, tadalafil, tolterodine Other colchicine, in subjects with renal or hepatic impairment colchicine cinacalcet, tolvaptan Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with SPORANOX® may increase the risk of potentially fatal adverse events. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drugs that may have their plasma concentrations decreased by itraconazole Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adjusted if necessary. Pediatric Population Interaction studies have only been performed in adults. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOX® therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS: Post-marketing Experience.) Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX® have not been established in pediatric patients. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. Geriatric Use: Clinical studies of SPORANOX® Capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. It is advised to use SPORANOX® Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal impairment. Caution should be exercised when itraconazole is administered in this patient population and dose adjustment may be needed. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. It is recommended that patients with impaired hepatic function be carefully monitored when taking SPORANOX®. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre- existing hepatic function abnormalities or those who have experienced liver toxicity with other medications. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX® use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. Table 2: Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea 11 Vomiting 5 Diarrhea 3 Abdominal Pain 2 Anorexia 1 Body as a Whole Edema 4 Fatigue 3 Fever 3 Malaise 1 Skin and Appendages Rash* 9 Pruritus 3 Central/Peripheral Nervous System Headache 4 Dizziness 2 Psychiatric Libido Decreased 1 Somnolence 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2: Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 * Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Table 3: Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. Table 4: Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Adverse Events Reported from Other Clinical Trials In addition, the following adverse drug reaction was reported in patients who participated in SPORANOX® Capsules clinical trials: Hepatobiliary Disorders: hyperbilirubinemia. The following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of SPORANOX® Oral Solution and itraconazole IV excluding the adverse reaction term “Injection site inflammation” which is specific to the injection route of administration: Cardiac Disorders: cardiac failure, left ventricular failure, tachycardia; General Disorders and Administration Site Conditions: face edema, chest pain, chills; Hepatobiliary Disorders: hepatic failure, jaundice; Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gamma-glutamyltransferase increased, urine analysis abnormal; Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia, hypomagnesemia; Psychiatric Disorders: confusional state; Renal and Urinary Disorders: renal impairment; Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Respiratory, Thoracic and Mediastinal Disorders: dysphonia, cough; Skin and Subcutaneous Tissue Disorders: rash erythematous, hyperhidrosis; Vascular Disorders: hypotension Post-marketing Experience Adverse drug reactions that have been first identified during post-marketing experience with SPORANOX® (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Table 5: Postmarketing Reports of Adverse Drug Reactions Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocytopenia Immune System Disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Nervous System Disorders: Peripheral neuropathy, paresthesia, hypoesthesia Eye Disorders: Visual disturbances, including vision blurred and diplopia Ear and Labyrinth Disorders: Transient or permanent hearing loss Cardiac Disorders: Congestive heart failure Respiratory, Thoracic and Mediastinal Disorders: Pulmonary edema, dyspnea Gastrointestinal Disorders: Pancreatitis, dysgeusia Hepatobiliary Disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria Musculoskeletal and Connective Tissue Disorders: Arthralgia Renal and Urinary Disorders: Urinary incontinence, pollakiuria Reproductive System and Breast Disorders: Erectile dysfunction Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 5: Postmarketing Reports of Adverse Drug Reactions General Disorders and Administration Site Conditions: Peripheral edema Investigations: Blood creatine phosphokinase increased There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX® has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.) OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures should be employed. Activated charcoal may be given if considered appropriate. In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole. (See ADVERSE REACTIONS.) DOSAGE AND ADMINISTRATION SPORANOX® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX® (itraconazole) Capsules must be swallowed whole. SPORANOX® Capsules is a different preparation than SPORANOX® Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX® Capsules and SPORANOX® Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX®. Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS.) Use in Patients with Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.) HOW SUPPLIED SPORANOX® (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.” The capsules are supplied in unit-dose blister packs of 3 × 10 capsules (NDC 50458-290- 01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak® containing 7 blister packs × 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children. © Janssen Pharmaceuticals, Inc 2001 Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Revised: June 2014 Product of Ireland Capsule contents manufactured by: Janssen Pharmaceutica N.V. Olen, Belgium Manufactured by: JOLLC, Gurabo, Puerto Rico 00778 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION 100 mg SPORANOX® (itraconazole) Capsules This summary contains important information about SPORANOX® (SPOR-ah-nox). This information is for patients who have been prescribed SPORANOX® to treat fungal nail infections. If your doctor prescribed SPORANOX® for medical problems other than fungal nail infections, ask your doctor if there is any information in this summary that does not apply to you. Read this information carefully each time you start to use SPORANOX®. This information does not take the place of discussion between you and your doctor. Only your doctor can decide if SPORANOX® is the right treatment for you. If you do not understand some of this information or have any questions, talk with your doctor or pharmacist. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT SPORANOX®? SPORANOX® is used to treat fungal nail infections. However, SPORANOX® is not for everyone. Do not take SPORANOX® for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take SPORANOX® if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See “Who Should Not Take SPORANOX®?” below.) If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is safe for you to take SPORANOX®. WHAT HAPPENS IF I HAVE A FUNGAL NAIL INFECTION? Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort. WHAT IS SPORANOX®? SPORANOX® is a prescription medicine used to treat fungal infections of the toenails and fingernails. It is also used to treat some types of fungal infections in other areas of your body. We do not know if SPORANOX® works in children with fungal nail infections or if it is safe for children to take. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX® comes in the form of capsules and liquid (oral solution). The capsule and liquid forms work differently, so you should not use one in place of the other. This Patient Information discusses only the capsule form of SPORANOX®. You will get these capsules in a medicine bottle or a SPORANOX PulsePak®. The PulsePak® contains 28 capsules for treatment of your fungal nail infection. SPORANOX® goes into your bloodstream and travels to the source of the infection underneath the nail so that it can fight the infection there. Improved nails may not be obvious for several months after the treatment period is finished because it usually takes about 6 months to grow a new fingernail and 12 months to grow a new toenail. WHO SHOULD NOT TAKE SPORANOX®? SPORANOX® is not for everyone. Your doctor will decide if SPORANOX® is the right treatment for you. Some patients should not take SPORANOX® because they may have certain health problems or may be taking certain medicines that could lead to serious or life-threatening medical problems. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking, including dietary supplements and herbal remedies. Also tell your doctor about any other medical conditions you have had, especially heart, lung, liver or kidney conditions; or if you have had an allergic reaction to SPORANOX® or any other antifungal medicines. Never take SPORANOX® if you: • have had heart failure, including congestive heart failure. • are taking any of the medicines listed below. Dangerous or even life-threatening abnormal heartbeats could result: • quinidine (such as Cardioquin®, Quinaglute®, Quinidex®) • dofetilide (such as Tikosyn™) • cisapride (such as Propulsid®) • pimozide (such as Orap®) • methadone (such as Dolophine®) • disopyramide (such as Norpace®) • dronedarone (such as Multaq®) • ranolazine (such as Ranexa®) • are taking any of the following medicines: Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • lovastatin (such as Mevacor®, Advicor®, Altocor™) • simvastatin (such as Zocor®) • triazolam (such as Halcion®) • midazolam (such as Versed®) • lurasidone (such as Latuda®) • nisoldipine (such as Sular®) • felodipine (such as Plendil®) • ergot alkaloids (such as Migranal®, Ergonovine, Cafergot®, Methergine®) • eplerenone (such as Inspra®) • irinotecan (such as Camptosar®) • colchicine (such as Colcrys™) [if you also have pre-existing kidney or liver impairment] • have ever had an allergic reaction to itraconazole. Taking SPORANOX® with certain other medicines could lead to serious or life-threatening medical problems. For example, taking fentanyl, a strong opioid narcotic pain medicine, with SPORANOX® could cause serious side effects, including trouble breathing, that may be life- threatening. Tell your doctor and pharmacist the name of all the prescription and non- prescription medicines you are taking. Your doctor will decide if SPORANOX® is the right treatment for you. WHAT SHOULD I KNOW ABOUT SPORANOX® AND PREGNANCY OR BREAST FEEDING? Never take SPORANOX® if you have a fungal nail infection and are pregnant or planning to become pregnant within 2 months after you have finished your treatment. If you are able to become pregnant, you should use effective birth control during SPORANOX® treatment and for 2 months after finishing treatment. Ask your doctor about effective types of birth control. If you are breast-feeding, talk with your doctor about whether you should take SPORANOX®. HOW SHOULD I TAKE SPORANOX®? Always take SPORANOX® Capsules during or right after a full meal. Your doctor will decide the right dose for you. Depending on your infection, you will take SPORANOX® once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda schedule. You will receive either a bottle of capsules or a PulsePak®. Do not skip any doses. Be sure to finish all your SPORANOX® as prescribed by your doctor. If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven’t had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking SPORANOX® can develop liver problems. SPORANOX® can sometimes cause dizziness or blurred/double vision. If you have these symptoms, do not drive or use machines. If you forget to take or miss doses of SPORANOX®, ask your doctor what you should do with the missed doses. THE SPORANOX PulsePak® If you use the PulsePak®, you will take SPORANOX® for 1 week and then take no SPORANOX® for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The SPORANOX PulsePak® contains enough medicine for one “pulse” (1 week of treatment). The SPORANOX PulsePak® comes with special instructions. It contains 7 pouches-one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of the card, fold it back along the dashed line and peel away the backing so that you can remove 2 capsules. • Take 2 capsules in the morning and 2 capsules in the evening. This means you will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all of the capsules in the PulsePak® box. • After you finish the PulsePak®, do not take any SPORANOX® for the next 3 weeks. Even though you are not taking any capsules during this time, SPORANOX® keeps working inside your nails to help fight the fungal infection. • You will need more than one “pulse” to treat your fungal nail infection. When your doctor prescribes another pulse treatment, be sure to get your refill before the end of week 4. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPORANOX® Pulse Dosing Take 2 SPORANOX® capsules twice a day for 1 week Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 AM PM AM PM AM PM AM PM AM PM AM PM AM PM Week 1 // // // // // // // // // // // // // // Week 2 For the next 3 weeks, do not take any SPORANOX® capsules. Remember to get a refill before the end of Week 4 when your doctor prescribes another PulsePak®. Week 3 Week 4 WHAT ARE THE POSSIBLE SIDE EFFECTS OF SPORANOX®? The most common side effects include: headache, and digestive system problems (such as nausea, and abdominal pain). Stop SPORANOX® and call your doctor or get medical assistance right away if you have a severe allergic reaction. Symptoms of an allergic reaction may include skin rash, itching, hives, shortness of breath or difficulty breathing, and/or swelling of the face. Very rarely, an oversensitivity to sunlight, a tingling sensation in the limbs or a severe skin disorder can occur. If any of these symptoms occur, stop taking SPORANOX® and contact your doctor. Stop SPORANOX® and call your doctor right away if you develop shortness of breath; have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up white or pink phlegm; have unusual fast heartbeats; or begin to wake up at night. In rare cases, patients taking SPORANOX® could develop serious heart problems, and these could be warning signs of heart failure. Stop SPORANOX® and call your doctor right away if you become unusually tired; lose your appetite; or develop nausea, abdominal pain, or vomiting, a yellow color to your skin or eyes, or dark colored urine or pale stools (bowel movements). In rare cases, patients taking SPORANOX® could develop serious liver problems and these could be warning signs. Stop SPORANOX® and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking SPORANOX® have reported temporary or permanent hearing loss. Call your doctor right away if you develop tingling or numbness in your extremities (hands or feet), if your vision gets blurry or you see double, if you hear a ringing in your ears, if you lose the ability to control your urine or urinate much more than usual. Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Additional possible side effects include upset stomach, vomiting, constipation, fever, inflammation of the pancreas, menstrual disorder, erectile dysfunction, dizziness, muscle pain, painful joints, unpleasant taste, or hair loss. These are not all the side effects of SPORANOX®. Your doctor or pharmacist can give you a more complete list. WHAT SHOULD I DO IF I TAKE AN OVERDOSE OF SPORANOX®? If you think you took too much SPORANOX®, call your doctor or local poison control center, or go to the nearest hospital emergency room right away. HOW SHOULD I STORE SPORANOX®? Keep all medicines, including SPORANOX®, out of the reach of children. Store SPORANOX® Capsules and the PulsePak® at room temperature in a dry place away from light. GENERAL ADVICE ABOUT SPORANOX® Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use SPORANOX® for a condition for which it was not prescribed. Do not give SPORANOX® to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about SPORANOX®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about SPORANOX® that is written for health professionals or you can call 1-800-526-7736. This patient information has been approved by the U.S. Food and Drug Administration. Product of Ireland © Janssen Pharmaceuticals, Inc 2001 Printed in USA/ Revised: June 2014 Reference ID: 3520611 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:43.207193	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020083s053lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 53}
12,204	DIFLUCAN® (Fluconazole Tablets) (Fluconazole Injection - for intravenous infusion only) (Fluconazole for Oral Suspension) DESCRIPTION DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight 306.3. The structural formula is: OH Che mica l St ru ct ru re Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in Viaflex® Plus plastic containers. The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL). Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Ratio of Fluconazole Tissue (Fluid)/Plasma Tissue or Fluid Concentration* Cerebrospinal fluid† 0.5-0.9 Saliva 1 Sputum 1 Blister fluid 1 Urine 10 Normal skin 10 Nails 1 Blister skin 2 Vaginal tissue 1 Vaginal fluid 0.4-0.7 * Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. Pharmacokinetics in Children In children, the following pharmacokinetic data {Mean(%cv)} have been reported: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) Cmax (μg/mL) Vdss (L/kg) 9 Months- 13 years Single-Oral 2 mg/kg 0.40 (38%) N=14 25.0 2.9 (22%) N=16 ___ 9 Months- 13 years Single-Oral 8 mg/kg 0.51 (60%) N=15 19.5 9.8 (20%) N=15 ___ 5-15 years Multiple IV 2 mg/kg 0.49 (40%) N=4 17.4 5.5 (25%) N=5 0.722 (36%) N=4 5-15 years Multiple IV 4 mg/kg 0.59 (64%) N=5 15.2 11.4 (44%) N=6 0.729 (33%) N=5 5-15 years Multiple IV 8 mg/kg 0.66 (31%) N=7 17.6 14.1 (22%) N=8 1.069 (37%) N=7 Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later. Pharmacokinetics in Elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4+ 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject’s terminal elimination half-life versus creatinine clearance compared with the predicted half-life – creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life – creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interaction Studies Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18-31%) and 13% (95% C.I. range 8-18%), respectively relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment. Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased 19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers. Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of fluconazole. Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10 to –50%). Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.) Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response. Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.) Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased 60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.) Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2. Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17% (range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See PRECAUTIONS.) Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400-mg and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.) Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily for 7 days. In these three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of placebo treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS.) Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.) Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean ± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.) Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean ± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19% (range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS.) Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See PRECAUTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.) Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.) Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.) Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Microbiology Mechanism of Action This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Activity In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections. Candida albicans Candida glabrata (Many strains are intermediately susceptible)* Candida parapsilosis Candida tropicalis Cryptococcus neoformans * In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint (≥16µg/ml). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/ml, see Table 1), the highest dose is recommended (see Dosage and Administration). For resistant isolates alternative therapy is recommended. The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well controlled trials. Candida dubliniensis Candida guilliermondii Candida kefyr Candida lusitaniae Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Susceptibility Testing Methods Cryptococcus neoformans and filamentous fungi: No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Candida species: Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1. Table 1: Susceptibility Interpretive Criteria for Fluconazole Broth Dilution at 48 hours (MIC in µg/mL) Disk Diffusion at 24 hours (Zone Diameters in mm) Antifungal agent Susceptible (S) Intermediate (I) Resistant (R) Susceptible (S) Intermediate (I) Resistant (R) Fluconazole* ≤ 8.0 16-32 ≥64 ≥19 15-18 ≤14 * Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale. ** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole. The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda QC Strain Macrodilution (MIC in µg/mL) @ 48 hours Microdilution (MIC in µg/mL) @ 48 hours Disk Diffusion (Zone Diameter in mm) @ 24 hours Candida parapsilosis ATCC 22019 2.0-8.0 1.0-4.0 22-33 Candida krusei ATCC 6258 16-64 16-128 ---* Candida albicans ATCC 90028 ---* ---* 28-39 Candida tropicalis ATCC 750 ---* ---* 26-37 ---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. Activity In Vivo Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown. Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis. Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Drug Resistance Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms. Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles. Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 µg/mL), the highest fluconazole dose is recommended. Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. INDICATIONS AND USAGE DIFLUCAN (fluconazole) is indicated for the treatment of: 1. Vaginal candidiasis (vaginal yeast infections due to Candida). 2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. CLINICAL STUDIES Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.) Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation. The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group. Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days Enrolled 448 422 Evaluable at Late Follow-up 347 (77%) 327 (77%) Clinical cure 239/347 (69%) 235/327 (72%) Mycologic erad. 213/347 (61%) 196/327 (60%) Therapeutic cure 190/347 (55%) 179/327 (55%) Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication and 59% therapeutic cure when treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parameter Fluconazole PO Vaginal Products Evaluable patients 448 422 With any adverse event 141 (31%) 112 (27%) Nervous System 90 (20%) 69 (16%) Gastrointestinal 73 (16%) 18 ( 4%) With drug-related event 117 (26%) 67 (16%) Nervous System 61 (14%) 29 ( 7%) Headache 58 (13%) 28 ( 7%) Gastrointestinal 68 (15%) 13 ( 3%) Abdominal pain 25 ( 6%) 7 ( 2%) Nausea 30 ( 7%) 3 ( 1%) Diarrhea 12 ( 3%) 2 (<1%) Application site event 0 ( 0%) 19 ( 5%) Taste Perversion 6 ( 1%) 0 ( 0%) Pediatric Studies Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole. Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients. Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication* 55/72 (76%) 6/54 (11%) * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response. The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23% for nystatin. CONTRAINDICATIONS DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of cisapride is This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda contraindicated in patients receiving DIFLUCAN (fluconazole). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.) WARNINGS (1) Hepatic injury: DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress. PRECAUTIONS General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Single Dose The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) Clinically or potentially significant drug interactions between This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Tacrolimus Short-acting benzodiazepines Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200-mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400-mg and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Cisapride: There have been reports of cardiac events, including torsade de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Astemizole: The use of fluconazole in patients concurrently taking astemizole or other drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when coadministering fluconazole. Patients should be carefully monitored. Rifabutin: There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus: There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-containing oral contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels; however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and levonorgestrel levels. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The data presently available indicate that the decreases in some individual ethinyl estradiol and levonorgestrel AUC values with fluconazole treatment are likely the result of random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or levonorgestrel metabolism. The clinical significance of these effects is presently unknown. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur. Carcinogenesis, Mutagenesis and Impairment of Fertility Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.) Pregnancy Teratogenic Effects. Pregnancy Category C: Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies, at 5, 10 and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were detected. In several studies in which pregnant rats were treated orally with fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis and parturition. There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis (an unindicated use). The relationship between fluconazole use and these events is unclear. DIFLUCAN should be used in pregnancy only if the potential benefit justifies the possible risk to the fetus. Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of DIFLUCAN in nursing mothers is not recommended. Pediatric Use An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.) The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.) Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN. Geriatric Use In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during postmarketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.) Central Nervous System: Seizures, dizziness. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dermatologic: Exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS), alopecia. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Dyspepsia, vomiting. Other Senses: Taste perversion. Adverse Reactions in Children: In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 OVERDOSAGE There have been reports of overdosage with DIFLUCAN (fluconazole). A 42-year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behavior after reportedly ingesting 8200 mg of DIFLUCAN. The patient was admitted to the hospital, and his condition resolved within 48 hours. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions. DOSAGE AND ADMINISTRATION Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended DIFLUCAN daily dosage for the prevention of candidiasis of patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children: The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12* mg/kg 400 mg * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140-age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Administration DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for intravenous administration using sterile equipment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. DO NOT ADD SUPPLEMENTARY MEDICATION. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Preparation for Administration: 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. HOW SUPPLIED DIFLUCAN® Tablets: Pink trapezoidal tablets containing 50, 100 or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN® Tablets are supplied as follows: DIFLUCAN® 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG” on the back. NDC 0049-3410-30 Bottles of 30 DIFLUCAN® 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and “ROERIG” on the back. NDC 0049-3420-30 Bottles of 30 NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN® 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and “ROERIG” on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN® 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and “ROERIG” on the back. NDC 0049-3430-30 Bottles of 30 NDC 0049-3430-41 Unit dose package of 100 Storage: Store tablets below 86°F (30°C). DIFLUCAN® for Oral Suspension: DIFLUCAN® for oral suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottle NDC 0049-3450-19 Fluconazole 1400 mg per bottle Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN® Injections: DIFLUCAN® injections for intravenous infusion administration are formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or 200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN® injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose diluents. DIFLUCAN® Injections in Glass Bottles: NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing. DIFLUCAN® Injections in Viaflex® Plus Plastic Containers: NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6 NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6 Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does not adversely affect the product. Protect from freezing. Rx only REFERENCES 1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27-A2, 2002 Volume 22, No 15, CLSI, Wayne, PA, August 2002. 2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion Susceptibllity Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume 24, No. 15 CLSI, Wayne, PA, May 2004. 3. Pfaller, M. A., Messer,S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Voriconazole among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of Clinical Microbiology. 45:70–75. Pfizer Company Logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LAB-0099-9.1 Revised March 2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:43.297615	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019949s041,019950s043,020090s022lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 22}
12,205	DIFLUCAN® (Fluconazole Tablets) (Fluconazole Injection - for intravenous infusion only) (Fluconazole for Oral Suspension) DESCRIPTION DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight 306.3. The structural formula is: str uct ural f or mu la Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in Viaflex® Plus plastic containers. The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN (fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken without regard to meals. (see DOSAGE AND ADMINISTRATION.) Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL). Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Ratio of Fluconazole Tissue (Fluid)/Plasma Tissue or Fluid Concentration* Cerebrospinal fluid† 0.5-0.9 Saliva 1 Sputum 1 Blister fluid 1 Urine 10 Normal skin 10 Nails 1 Blister skin 2 Vaginal tissue 1 Vaginal fluid 0.4-0.7 * Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics in Children In children, the following pharmacokinetic data {Mean(%cv)} have been reported: Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) Cmax (μg/mL) Vdss (L/kg) 9 Months- 13 years Single-Oral 2 mg/kg 0.40 (38%) N=14 25.0 2.9 (22%) N=16 ___ 9 Months- 13 years Single-Oral 8 mg/kg 0.51 (60%) N=15 19.5 9.8 (20%) N=15 ___ 5-15 years Multiple IV 2 mg/kg 0.49 (40%) N=4 17.4 5.5 (25%) N=5 0.722 (36%) N=4 5-15 years Multiple IV 4 mg/kg 0.59 (64%) N=5 15.2 11.4 (44%) N=6 0.729 (33%) N=5 5-15 years Multiple IV 8 mg/kg 0.66 (31%) N=7 17.6 14.1 (22%) N=8 1.069 (37%) N=7 Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later. Pharmacokinetics in Elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4+ 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject’s terminal elimination half-life versus creatinine clearance compared with the predicted half-life – creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life – creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly. Drug Interaction Studies Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18-31%) and 13% (95% C.I. range 8-18%), respectively relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment. Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased 19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers. Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of fluconazole. Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31% (range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10 to –50%). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.) Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response. Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.) Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased 60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.) Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2. Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17% (range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See PRECAUTIONS.) Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400-mg and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.) Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily for 7 days. In these three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of placebo treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS.) Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.) Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean ± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.) Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean ± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19% (range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS.) Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See PRECAUTIONS.) Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.) Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.) Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.) Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Microbiology Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Activity In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections. Candida albicans Candida glabrata (Many strains are intermediately susceptible)* Candida parapsilosis Candida tropicalis Cryptococcus neoformans * In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint (≥16µg/ml). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/ml, see Table 1), the highest dose is recommended (see Dosage and Administration). For resistant isolates alternative therapy is recommended. The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well controlled trials. Candida dubliniensis Candida guilliermondii Candida kefyr Candida lusitaniae Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Susceptibility Testing Methods Cryptococcus neoformans and filamentous fungi: No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi. Candida species: Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1. Table 1: Susceptibility Interpretive Criteria for Fluconazole Broth Dilution at 48 hours (MIC in µg/mL) Disk Diffusion at 24 hours (Zone Diameters in mm) Antifungal agent Susceptible (S) Intermediate (I) Resistant (R) Susceptible (S) Intermediate (I) Resistant (R) Fluconazole* ≤ 8.0 16-32 ≥64 ≥19 15-18 ≤14 * Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale. ** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole. The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results QC Strain Macrodilution (MIC in µg/mL) @ 48 hours Microdilution (MIC in µg/mL) @ 48 hours Disk Diffusion (Zone Diameter in mm) @ 24 hours Candida parapsilosis ATCC 22019 2.0-8.0 1.0-4.0 22-33 Candida krusei ATCC 6258 16-64 16-128 ---* Candida albicans ATCC 90028 ---* ---* 28-39 Candida tropicalis ATCC 750 ---* ---* 26-37 ---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. Activity In Vivo Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown. Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis. Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Drug Resistance Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms. Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles. Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 µg/mL), the highest fluconazole dose is recommended. Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. INDICATIONS AND USAGE DIFLUCAN (fluconazole) is indicated for the treatment of: 1. Vaginal candidiasis (vaginal yeast infections due to Candida). 2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL STUDIES Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.) Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation. The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group. Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days Enrolled 448 422 Evaluable at Late Follow-up 347 (77%) 327 (77%) Clinical cure 239/347 (69%) 235/327 (72%) Mycologic erad. 213/347 (61%) 196/327 (60%) Therapeutic cure 190/347 (55%) 179/327 (55%) Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication and 59% therapeutic cure when treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parameter Fluconazole PO Vaginal Products Evaluable patients 448 422 With any adverse event 141 (31%) 112 (27%) Nervous System 90 (20%) 69 (16%) Gastrointestinal 73 (16%) 18 ( 4%) With drug-related event 117 (26%) 67 (16%) Nervous System 61 (14%) 29 ( 7%) Headache 58 (13%) 28 ( 7%) Gastrointestinal 68 (15%) 13 ( 3%) Abdominal pain 25 ( 6%) 7 ( 2%) Nausea 30 ( 7%) 3 ( 1%) Diarrhea 12 ( 3%) 2 (<1%) Application site event 0 ( 0%) 19 ( 5%) Taste Perversion 6 ( 1%) 0 ( 0%) Pediatric Studies Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole. Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients. Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication* 55/72 (76%) 6/54 (11%) * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response. The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23% for nystatin. CONTRAINDICATIONS DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of cisapride is This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda contraindicated in patients receiving DIFLUCAN (fluconazole). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.) WARNINGS (1) Hepatic injury: DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress. PRECAUTIONS General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Single Dose The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) Clinically or potentially significant drug interactions between This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Tacrolimus Short-acting benzodiazepines Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200-mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400-mg and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Cisapride: There have been reports of cardiac events, including torsade de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Astemizole: The use of fluconazole in patients concurrently taking astemizole or other drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when coadministering fluconazole. Patients should be carefully monitored. Rifabutin: There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus: There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-containing oral contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels; however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and levonorgestrel levels. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The data presently available indicate that the decreases in some individual ethinyl estradiol and levonorgestrel AUC values with fluconazole treatment are likely the result of random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or levonorgestrel metabolism. The clinical significance of these effects is presently unknown. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur. Carcinogenesis, Mutagenesis and Impairment of Fertility Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.) Pregnancy Teratogenic Effects. Pregnancy Category C: Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies, at 5, 10 and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were detected. In several studies in which pregnant rats were treated orally with fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis and parturition. There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis (an unindicated use). The relationship between fluconazole use and these events is unclear. DIFLUCAN should be used in pregnancy only if the potential benefit justifies the possible risk to the fetus. Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of DIFLUCAN in nursing mothers is not recommended. Pediatric Use An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.) The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.) Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN. Geriatric Use In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during postmarketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.) Central Nervous System: Seizures, dizziness. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dermatologic: Exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS), alopecia. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Dyspepsia, vomiting. Other Senses: Taste perversion. Adverse Reactions in Children: In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 OVERDOSAGE There have been reports of overdosage with DIFLUCAN (fluconazole). A 42-year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behavior after reportedly ingesting 8200 mg of DIFLUCAN. The patient was admitted to the hospital, and his condition resolved within 48 hours. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions. DOSAGE AND ADMINISTRATION Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended DIFLUCAN daily dosage for the prevention of candidiasis of patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children: The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12* mg/kg 400 mg * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140-age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Administration DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for intravenous administration using sterile equipment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. DO NOT ADD SUPPLEMENTARY MEDICATION. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Preparation for Administration: 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. HOW SUPPLIED DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100 or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN Tablets are supplied as follows: DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG” on the back. NDC 0049-3410-30 Bottles of 30 DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and “ROERIG” on the back. NDC 0049-3420-30 Bottles of 30 NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and “ROERIG” on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and “ROERIG” on the back. NDC 0049-3430-30 Bottles of 30 NDC 0049-3430-41 Unit dose package of 100 Storage: Store tablets below 86°F (30°C). DIFLUCAN for Oral Suspension: DIFLUCAN for oral suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottle NDC 0049-3450-19 Fluconazole 1400 mg per bottle Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or 200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose diluents. DIFLUCAN Injections in Glass Bottles: NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing. DIFLUCAN Injections in Viaflex® Plus Plastic Containers: NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6 NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6 Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does not adversely affect the product. Protect from freezing. Rx only REFERENCES 1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27 A2, 2002 Volume 22, No 15, CLSI, Wayne, PA, August 2002. 2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion Susceptibllity Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume 24, No. 15 CLSI, Wayne, PA, May 2004. 3. Pfaller, M. A., Messer,S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Voriconazole among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of Clinical Microbiology. 45:70–75. company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LAB-0099-11.0 Revised August, 2010 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:43.394298	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019949s048,019950s053,020090s031lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 31}
12,208	s t ruc tur al f or mu la DIFLUCAN® (Fluconazole Tablets) (Fluconazole Injection - for intravenous infusion only) (Fluconazole for Oral Suspension) DESCRIPTION DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The structural formula is: Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in Viaflex® Plus plastic containers. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN (fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken without regard to meals. (see DOSAGE AND ADMINISTRATION.) Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL). Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Ratio of Fluconazole Tissue (Fluid)/Plasma Tissue or Fluid Concentration* Cerebrospinal fluid† 0.5-0.9 Saliva 1 Sputum 1 Blister fluid 1 Urine 10 Normal skin 10 Nails 1 Blister skin 2 Vaginal tissue 1 Vaginal fluid 0.4-0.7 * Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics in Children In children, the following pharmacokinetic data {Mean (%cv)} have been reported: Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) Cmax (µg/mL) Vdss (L/kg) 9 Months 13 years Single-Oral 2 mg/kg 0.40 (38%) N=14 25.0 2.9 (22%) N=16 ___ 9 Months 13 years Single-Oral 8 mg/kg 0.51 (60%) N=15 19.5 9.8 (20%) N=15 ___ 5-15 years Multiple IV 2 mg/kg 0.49 (40%) N=4 17.4 5.5 (25%) N=5 0.722 (36%) N=4 5-15 years Multiple IV 4 mg/kg 0.59 (64%) N=5 15.2 11.4 (44%) N=6 0.729 (33%) N=5 5-15 years Multiple IV 8 mg/kg 0.66 (31%) N=7 17.6 14.1 (22%) N=8 1.069 (37%) N=7 Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later. Pharmacokinetics in Elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4 ± 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject’s terminal elimination half-life versus creatinine clearance compared with the predicted half-life – creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life – creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly. Drug Interaction Studies Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%) and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment. Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased 19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers. Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of fluconazole. Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31% (range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10 to –50%). Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.) Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response. Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.) Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased 60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.) Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2. Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17% (range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See PRECAUTIONS.) Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.) Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS and PRECAUTIONS.) Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS.) Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.) Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean ± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.) Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean ± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19% (range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS.) Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See PRECAUTIONS.) Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.) Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.) Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.) Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes. Concurrent administration of oral Voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 h of the last dose of fluconazole. (See PRECAUTIONS) Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tofacitinib: Co-administration of fluconazole (400 mg on Day 1 and 200 mg once daily for 6 days [Days 2-7]) and tofacitinib (30 mg single dose on Day 5) in healthy subjects resulted in increased mean tofacitinib AUC and Cmax values of approximately 79% (90% CI: 64% – 96%) and 27% (90% CI: 12% – 44%), respectively, compared to administration of tofacitinib alone. (See PRECAUTIONS) Microbiology Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Drug Resistance Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms. Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell. The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles. Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 µg/mL), the highest fluconazole dose is recommended. Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Activity In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections. Candida albicans Candida glabrata (Many strains are intermediately susceptible)* Candida parapsilosis Candida tropicalis Cryptococcus neoformans * In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint (≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative therapy is recommended. The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. Candida dubliniensis Candida guilliermondii Candida kefyr Candida lusitaniae Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Susceptibility Testing Methods Cryptococcus neoformans and filamentous fungi: No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi. Candida species: Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1. Table 1: Susceptibility Interpretive Criteria for Fluconazole Broth Dilution at 48 hours (MIC in µg/mL) Disk Diffusion at 24 hours (Zone Diameters in mm) Antifungal agent Susceptible (S) Intermediate (I) Resistant (R) Susceptible (S) Intermediate (I) Resistant (R) Fluconazole* ≤ 8.0 16-32 ≥64 ≥19 15-18 ≤14 * Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale. ** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole. The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results QC Strain Macrodilution (MIC in µg/mL) @ 48 hours Microdilution (MIC in µg/mL) @ 48 hours Disk Diffusion (Zone Diameter in mm) @ 24 hours Candida parapsilosis ATCC 22019 2.0-8.0 1.0-4.0 22-33 Candida krusei ATCC 6258 16-64 16-128 ---* Candida albicans ATCC 90028 ---* ---* 28-39 Candida tropicalis ATCC 750 ---* ---* 26-37 ---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE DIFLUCAN (fluconazole) is indicated for the treatment of: 1. Vaginal candidiasis (vaginal yeast infections due to Candida). 2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. CLINICAL STUDIES Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.) Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation. The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days Enrolled 448 422 Evaluable at Late Follow-up 347 (77%) 327 (77%) Clinical cure 239/347 (69%) 235/327 (72%) Mycologic eradication 213/347 (61%) 196/327 (60%) Therapeutic cure 190/347 (55%) 179/327 (55%) Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred. Parameter Fluconazole PO Vaginal Products Evaluable patients 448 422 With any adverse event 141 (31%) 112 (27%) Nervous System 90 (20%) 69 (16%) Gastrointestinal 73 (16%) 18 (4%) With drug-related event 117 (26%) 67 (16%) Nervous System 61 (14%) 29 (7%) Headache 58 (13%) 28 (7%) Gastrointestinal 68 (15%) 13 (3%) Abdominal pain 25 (6%) 7 (2%) Nausea 30 (7%) 3 (1%) Diarrhea 12 (3%) 2 (<1%) Application site event 0 (0%) 19 (5%) Taste Perversion 6 (1%) 0 (0%) Pediatric Studies Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole. Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication* 55/72 (76%) 6/54 (11%) * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response. The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23% for nystatin. CONTRAINDICATIONS DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole.. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.) WARNINGS (1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Exfoliative skin disorders during treatment with DIFLUCAN have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (4) Use in Pregnancy: There are no adequate and well-controlled studies of DIFLUCAN in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus (See PRECAUTIONS, Pregnancy.) PRECAUTIONS General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided. Fluconazole should be administered with caution to patients with renal dysfunction. Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored. DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur. Single Dose The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Voriconazole Tacrolimus Short-acting benzodiazepines Tofacitinib Triazolam Oral Contraceptives Pimozide Quinidine Hydrochlorothiazide Alfentanil Amitriptyline, nortriptyline Amphotericin B Azithromycin Carbamazepine Calcium Channel Blockers Celecoxib Cyclophosphamide Fentanyl Halofantrine HMG-CoA reductase inhibitors Losartan Methadone Non-steroidal anti-inflammatory drugs Prednisone Saquinavir Sirolimus Vinca Alkaloids Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Vitamin A Zidovudine Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Cyclosporine: DIFLUCAN significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies). This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration. Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated. . Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tofacitinib: Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole, a combined moderate CYP3A4 and potent CYP2C19 inhibitor. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the XELJANZ® [tofacitinib] label). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Triazolam: Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20-32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary. Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated. Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS.) Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics. Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5 nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S (+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary. Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements. Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur. Carcinogenesis, Mutagenesis, and Impairment of Fertility Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.) Pregnancy Teratogenic Effects.Pregnancy Category C: Single 150 mg tablet use for Vaginal Candidiasis: There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. Pregnancy Category D: All other indications: A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy.) Human Data Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated with low dose exposure to fluconazole in pregnancy (most subjects received a single oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies. Animal Data Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed. In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations. Caution should be exercised when DIFLUCAN is administered to a nursing woman. Pediatric Use An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.) The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.) Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS DIFLUCAN is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during post-marketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Body as a Whole: Asthenia, fatigue, fever, malaise. Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.) Central Nervous System: Seizures, dizziness. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. Other Senses: Taste perversion. Musculoskeletal System: myalgia. Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo. Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS), alopecia. Adverse Reactions in Children: The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%. In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions. DOSAGE AND ADMINISTRATION Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children: The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12* mg/kg 400 mg * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) >50 Percent of Recommended Dose 100% ≤50 (no dialysis) Regular dialysis 50% 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140 – age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for intravenous administration using sterile equipment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DO NOT ADD SUPPLEMENTARY MEDICATION. Preparation for Administration: 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. HOW SUPPLIED DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN Tablets are supplied as follows: DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG” on the back. NDC 0049-3410-30 Bottles of 30 DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and “ROERIG” on the back. NDC 0049-3420-30 Bottles of 30 NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and “ROERIG” on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and “ROERIG” on the back. NDC 0049-3430-30 Bottles of 30 NDC 0049-3430-41 Unit dose package of 100 Storage: Store tablets below 86°F (30°C). DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottle NDC 0049-3450-19 Fluconazole 1400 mg per bottle Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or 200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose diluents. DIFLUCAN Injections in Glass Bottles: NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing. DIFLUCAN Injections in Viaflex® Plus Plastic Containers: NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6 NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6 Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does not adversely affect the product. Protect from freezing. REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI Document M27-A3, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, PA,19087-1898 USA, 2008 2. Clinical and Laboratory Standards Institute (CLSI). Methods for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guideline-Second Edition. CLSI Document M44-A2, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, PA, 19087-1898 USA, 2009 3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of Clinical Microbiology. 45:70–75. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0099-19.0 Revised March 2014 Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION DIFLUCAN (fluconazole tablets) This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not meant to take the place of your doctor's instructions. Read this information carefully before you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about DIFLUCAN. What Is DIFLUCAN? DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the yeast infection goes away. DIFLUCAN is different from other treatments for vaginal yeast infections because it is a tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet is only about using DIFLUCAN for vaginal yeast infections. For information about using DIFLUCAN for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information about vaginal yeast infections. What Is a Vaginal Yeast Infection? It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are common. About three out of every four adult women will have at least one vaginal yeast infection during their life. Some medicines and medical conditions can increase your chance of getting a yeast infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast infections more often than other women. Personal hygiene and certain types of clothing may increase your chances of getting a yeast infection. Ask your doctor for tips on what you can do to help prevent vaginal yeast infections. If you get a vaginal yeast infection, you may have any of the following symptoms: • itching • a burning feeling when you urinate • redness • soreness • a thick white vaginal discharge that looks like cottage cheese What To Tell Your Doctor Before You Start DIFLUCAN? Do not take Diflucan if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including: Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • diabetes medicines such as glyburide, tolbutamide, glipizide • blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine or felodipine • blood thinners such as warfarin • cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants) • rifampin or rifabutin for tuberculosis • astemizole for allergies • phenytoin or carbamazepine to control seizures • theophylline to control asthma • cisapride for heartburn • quinidine (used to correct disturbances in heart rhythm) • amitriptyline or nortriptyline for depression • pimozide for psychiatric illness • amphotericin B or voriconazole for fungal infections • erythromycin for bacterial infections • cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of cancer • fentanyl, afentanil or methadone for chronic pain • halofantrine for malaria • lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin • non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen • prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory disorders • antiviral medications used to treat HIV like saquinavir or zidovudine • tofacitinib for rheumatoid arthritis • vitamin A nutritional supplement Since there are many brand names for these medicines, check with your doctor or pharmacist if you have any questions. • are taking any over-the-counter medicines you can buy without a prescription, including natural or herbal remedies • have any liver problems. • have any other medical conditions • are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether DIFLUCAN is right for you. • are breast-feeding. DIFLUCAN can pass through breast milk to the baby. • are allergic to any other medicines including those used to treat yeast and other fungal infections. • are allergic to any of the ingredients in DIFLUCAN. The main ingredient of DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Who Should Not Take DIFLUCAN? To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking erythromycin, astemizole, pimozide, quinidine, and cisapride (Propulsid®) since it can cause changes in heartbeat in some people if taken with DIFLUCAN. How Should I Take DIFLUCAN Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time of the day. DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms start to go away after 24 hours. However, it may take several days for your symptoms to go away completely. If there is no change in your symptoms after a few days, call your doctor. Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection. What Should I Avoid while Taking DIFLUCAN? Some medicines can affect how well DIFLUCAN works. Check with your doctor before starting any new medicines within seven days of taking DIFLUCAN. What Are the Possible Side Effects of DIFLUCAN? Like all medicines, DIFLUCAN may cause some side effects that are usually mild to moderate. The most common side effects of DIFLUCAN are: • headache • diarrhea • nausea or upset stomach • dizziness • stomach pain • changes in the way food tastes Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs of an allergic reaction can include shortness of breath; coughing; wheezing; fever; chills; throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the body; or skin rash, hives, blisters or skin peeling. Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in patients with serious medical problems. Call your doctor if your skin or eyes become yellow, your urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit or feel like vomiting or if you have severe skin itching. Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin peeling have been reported. Tell your doctor right away if you get a rash while taking DIFLUCAN. DIFLUCAN may cause other less common side effects besides those listed here. If you develop any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor or pharmacist. What to Do For an Overdose In case of an accidental overdose, call your doctor right away or go to the nearest emergency room. How to Store DIFLUCAN Keep DIFLUCAN and all medicines out of the reach of children. General Advice about Prescription Medicines Medicines are sometimes prescribed for conditions that are mentioned in patient information leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not give DIFLUCAN to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about DIFLUCAN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about DIFLUCAN that is written for health professionals. You can also visit the DIFLUCAN Internet site at www.diflucan.com. company logo LAB-0380-6.0 Revised March 2014 Reference ID: 3476158 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:43.662170	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019949s058,019950s062,020090s042lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 42}
12,206	DIFLUCAN® (Fluconazole Tablets) (Fluconazole Injection - for intravenous infusion only) (Fluconazole for Oral Suspension) DESCRIPTION DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The structural formula is: OH str uctu ra l fo rm ul a Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in Viaflex® Plus plastic containers. The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN (fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken without regard to meals. (see DOSAGE AND ADMINISTRATION.) Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL). Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Ratio of Fluconazole Tissue (Fluid)/Plasma Tissue or Fluid Concentration* Cerebrospinal fluid† 0.5-0.9 Saliva 1 Sputum 1 Blister fluid 1 Urine 10 Normal skin 10 Nails 1 Blister skin 2 Vaginal tissue 1 Vaginal fluid 0.4-0.7 * Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics in Children In children, the following pharmacokinetic data {Mean (%cv)} have been reported: Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) Cmax (μg/mL) Vdss (L/kg) 9 Months- 13 years Single-Oral 2 mg/kg 0.40 (38%) N=14 25.0 2.9 (22%) N=16 ___ 9 Months- 13 years Single-Oral 8 mg/kg 0.51 (60%) N=15 19.5 9.8 (20%) N=15 ___ 5-15 years Multiple IV 2 mg/kg 0.49 (40%) N=4 17.4 5.5 (25%) N=5 0.722 (36%) N=4 5-15 years Multiple IV 4 mg/kg 0.59 (64%) N=5 15.2 11.4 (44%) N=6 0.729 (33%) N=5 5-15 years Multiple IV 8 mg/kg 0.66 (31%) N=7 17.6 14.1 (22%) N=8 1.069 (37%) N=7 Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later. Pharmacokinetics in Elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4 ± 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject’s terminal elimination half-life versus creatinine clearance compared with the predicted half-life – creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life – creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly. Drug Interaction Studies Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%) and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment. Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased 19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers. Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of fluconazole. Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31% (range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10 to –50%). Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.) Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response. Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.) Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased 60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.) Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2. Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17% (range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See PRECAUTIONS.) Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.) Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS.) Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.) Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean ± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.) Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean ± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19% (range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS.) Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See PRECAUTIONS.) Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.) Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.) Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.) Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes. Concurrent administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 h of the last dose of fluconazole. (See PRECAUTIONS.) Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Microbiology Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Activity In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections. Candida albicans Candida glabrata (Many strains are intermediately susceptible)* Candida parapsilosis Candida tropicalis Cryptococcus neoformans * In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint (≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative therapy is recommended. The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. Candida dubliniensis Candida guilliermondii Candida kefyr Candida lusitaniae Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Susceptibility Testing Methods Cryptococcus neoformans and filamentous fungi: No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi. Candida species: Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1. Table 1: Susceptibility Interpretive Criteria for Fluconazole Broth Dilution at 48 hours (MIC in µg/mL) Disk Diffusion at 24 hours (Zone Diameters in mm) Antifungal agent Susceptible (S) Intermediate (I) Resistant (R) Susceptible (S) Intermediate (I) Resistant (R) Fluconazole* ≤ 8.0 16-32 ≥64 ≥19 15-18 ≤14 * Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale. ** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole. The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results QC Strain Macrodilution (MIC in µg/mL) @ 48 hours Microdilution (MIC in µg/mL) @ 48 hours Disk Diffusion (Zone Diameter in mm) @ 24 hours Candida parapsilosis ATCC 22019 2.0-8.0 1.0-4.0 22-33 Candida krusei ATCC 6258 16-64 16-128 ---* Candida albicans ATCC 90028 ---* ---* 28-39 Candida tropicalis ATCC 750 ---* ---* 26-37 ---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. Activity In Vivo Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown. Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis. Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Drug Resistance Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell. The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles. Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 µg/mL), the highest fluconazole dose is recommended. Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. INDICATIONS AND USAGE DIFLUCAN (fluconazole) is indicated for the treatment of: 1. Vaginal candidiasis (vaginal yeast infections due to Candida). 2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. CLINICAL STUDIES Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.) Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation. The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group. Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days Enrolled 448 422 Evaluable at Late Follow-up 347 (77%) 327 (77%) Clinical cure 239/347 (69%) 235/327 (72%) Mycologic eradication 213/347 (61%) 196/327 (60%) Therapeutic cure 190/347 (55%) 179/327 (55%) Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred. Parameter Fluconazole PO Vaginal Products Evaluable patients 448 422 With any adverse event 141 (31%) 112 (27%) Nervous System 90 (20%) 69 (16%) Gastrointestinal 73 (16%) 18 (4%) With drug-related event 117 (26%) 67 (16%) Nervous System 61 (14%) 29 (7%) Headache 58 (13%) 28 (7%) Gastrointestinal 68 (15%) 13 (3%) Abdominal pain 25 (6%) 7 (2%) Nausea 30 (7%) 3 (1%) Diarrhea 12 (3%) 2 (<1%) Application site event 0 (0%) 19 (5%) Taste Perversion 6 (1%) 0 (0%) Pediatric Studies Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole. Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients. Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication* 55/72 (76%) 6/54 (11%) * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response. The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23% for nystatin. CONTRAINDICATIONS DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda between fluconazole and other azole antifungal agents. Caution should be used in prescribing DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, pimozide, and quinidine are contraindicated in patients receiving fluconazole.. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.) WARNINGS (1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress. (4) Use in Pregnancy: There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in-utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See PRECAUTIONS, Pregnancy) Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided. Fluconazole should be administered with caution to patients with renal dysfunction. Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored. DIFLUCAN Capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency. DIFLUCAN Syrup contains glycerol. Glycerol may cause headache, stomach upset, and diarrhea. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur. Single Dose The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Voriconazole Tacrolimus Short-acting benzodiazepines Triazolam Oral Contraceptives Pimozide Hydrochlorothiazide Alfentanil Amitriptyline, nortriptyline Amphotericin B Azithromycin Carbamazepine Calcium Channel Blockers Celecoxib Cyclophosphamide Fentanyl Halofantrine HMG-CoA reductase inhibitors Losartan Methadone Non-steroidal anti-inflammatory drugs Prednisone Saquinavir Sirolimus Vinca Alkaloids Vitamin A Zidovudine Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated. . Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20 32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary. Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. . Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated. Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics. Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S (+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary. Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements. Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur. Carcinogenesis, Mutagenesis, and Impairment of Fertility Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.) PRECAUTIONS/Pregnancy: Teratogenic Effects. Pregnancy Category C Single 150 mg tablet use for Vaginal Candidiasis: There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. Pregnancy Category D: All other indications: A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in-utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy) Human Data Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated with low dose exposure to fluconazole in pregnancy (most subjects received a single oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies. Animal Data Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed. In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition. PRECAUTIONS/Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations. Caution should be exercised when DIFLUCAN is administered to a nursing woman. Pediatric Use An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.) The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.) Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN. Geriatric Use Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS DIFLUCAN is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during post-marketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Body as a Whole: Asthenia, fatigue, fever, malaise. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.) Central Nervous System: Seizures, dizziness. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. Other Senses: Taste perversion. Musculoskeletal System: myalgia. Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo. Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS), alopecia. Adverse Reactions in Children: The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 OVERDOSAGE Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%. In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions. DOSAGE AND ADMINISTRATION Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children: The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12* mg/kg 400 mg * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140 – age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for intravenous administration using sterile equipment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. DO NOT ADD SUPPLEMENTARY MEDICATION. Preparation for Administration: 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. HOW SUPPLIED DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN Tablets are supplied as follows: DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG” on the back. NDC 0049-3410-30 Bottles of 30 DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and “ROERIG” on the back. NDC 0049-3420-30 Bottles of 30 NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and “ROERIG” on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and “ROERIG” on the back. NDC 0049-3430-30 Bottles of 30 NDC 0049-3430-41 Unit dose package of 100 Storage: Store tablets below 86°F (30°C). Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottle NDC 0049-3450-19 Fluconazole 1400 mg per bottle Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or 200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose diluents. DIFLUCAN Injections in Glass Bottles: NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing. DIFLUCAN Injections in Viaflex® Plus Plastic Containers: NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6 NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6 Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does not adversely affect the product. Protect from freezing. Rx only REFERENCES 1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27 A2, 2002 Volume 22, No. 15, CLSI, Wayne, PA, August 2002. 2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume 24, No. 15, CLSI, Wayne, PA, May 2004. Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of Clinical Microbiology. 45:70–75. Pfizer LAB-0099-13.0 Revised May 2011 Reference ID: 2956251 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:43.773105	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020090s034lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 34}
12,207	s t ruc tur al f or mu la DIFLUCAN® (Fluconazole Tablets) (Fluconazole Injection - for intravenous infusion only) (Fluconazole for Oral Suspension) DESCRIPTION DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The structural formula is: Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in Viaflex® Plus plastic containers. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN (fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken without regard to meals. (see DOSAGE AND ADMINISTRATION.) Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL). Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Ratio of Fluconazole Tissue (Fluid)/Plasma Tissue or Fluid Concentration* Cerebrospinal fluid† 0.5-0.9 Saliva 1 Sputum 1 Blister fluid 1 Urine 10 Normal skin 10 Nails 1 Blister skin 2 Vaginal tissue 1 Vaginal fluid 0.4-0.7 * Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics in Children In children, the following pharmacokinetic data {Mean (%cv)} have been reported: Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) Cmax (μg/mL) Vdss (L/kg) 9 Months- 13 years Single-Oral 2 mg/kg 0.40 (38%) N=14 25.0 2.9 (22%) N=16 ___ 9 Months- 13 years Single-Oral 8 mg/kg 0.51 (60%) N=15 19.5 9.8 (20%) N=15 ___ 5-15 years Multiple IV 2 mg/kg 0.49 (40%) N=4 17.4 5.5 (25%) N=5 0.722 (36%) N=4 5-15 years Multiple IV 4 mg/kg 0.59 (64%) N=5 15.2 11.4 (44%) N=6 0.729 (33%) N=5 5-15 years Multiple IV 8 mg/kg 0.66 (31%) N=7 17.6 14.1 (22%) N=8 1.069 (37%) N=7 Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later. Pharmacokinetics in Elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4 ± 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject’s terminal elimination half-life versus creatinine clearance compared with the predicted half-life – creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life – creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly. Drug Interaction Studies Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%) and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment. Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased 19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers. Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of fluconazole. Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31% (range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10 to –50%). Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.) Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response. Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.) Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased 60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.) Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2. Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17% (range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See PRECAUTIONS.) Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.) Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS.) Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.) Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean ± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.) Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean ± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19% (range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS.) Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See PRECAUTIONS.) Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.) Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.) Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.) Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes. Concurrent administration of oral Voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 h of the last dose of fluconazole. (See PRECAUTIONS) Microbiology Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Activity In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections. Candida albicans Candida glabrata (Many strains are intermediately susceptible)* Candida parapsilosis Candida tropicalis Cryptococcus neoformans * In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint (≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative therapy is recommended. The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. Candida dubliniensis Candida guilliermondii Candida kefyr Candida lusitaniae Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Susceptibility Testing Methods Cryptococcus neoformans and filamentous fungi: No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi. Candida species: Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1. Table 1: Susceptibility Interpretive Criteria for Fluconazole Broth Dilution at 48 hours (MIC in µg/mL) Disk Diffusion at 24 hours (Zone Diameters in mm) Antifungal agent Susceptible (S) Intermediate (I) Resistant (R) Susceptible (S) Intermediate (I) Resistant (R) Fluconazole* ≤ 8.0 16-32 ≥64 ≥19 15-18 ≤14 * Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale. ** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole. The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results QC Strain Macrodilution (MIC in µg/mL) @ 48 hours Microdilution (MIC in µg/mL) @ 48 hours Disk Diffusion (Zone Diameter in mm) @ 24 hours Candida parapsilosis ATCC 22019 2.0-8.0 1.0-4.0 22-33 Candida krusei ATCC 6258 16-64 16-128 ---* Candida albicans ATCC 90028 ---* ---* 28-39 Candida tropicalis ATCC 750 ---* ---* 26-37 ---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Activity In Vivo Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown. Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis. Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Drug Resistance Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms. Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell. The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles. Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 µg/mL), the highest fluconazole dose is recommended. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. INDICATIONS AND USAGE DIFLUCAN (fluconazole) is indicated for the treatment of: 1. Vaginal candidiasis (vaginal yeast infections due to Candida). 2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. CLINICAL STUDIES Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.) Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation. The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group. Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days Enrolled 448 422 Evaluable at Late Follow-up 347 (77%) 327 (77%) Clinical cure 239/347 (69%) 235/327 (72%) Mycologic eradication 213/347 (61%) 196/327 (60%) Therapeutic cure 190/347 (55%) 179/327 (55%) Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred. Parameter Fluconazole PO Vaginal Products Evaluable patients 448 422 With any adverse event 141 (31%) 112 (27%) Nervous System 90 (20%) 69 (16%) Gastrointestinal 73 (16%) 18 (4%) With drug-related event 117 (26%) 67 (16%) Nervous System 61 (14%) 29 (7%) Headache 58 (13%) 28 (7%) Gastrointestinal 68 (15%) 13 (3%) Abdominal pain 25 (6%) 7 (2%) Nausea 30 (7%) 3 (1%) Diarrhea 12 (3%) 2 (<1%) Application site event 0 (0%) 19 (5%) Taste Perversion 6 (1%) 0 (0%) Pediatric Studies Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients. Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication* 55/72 (76%) 6/54 (11%) * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response. The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23% for nystatin. CONTRAINDICATIONS DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, pimozide, and quinidine are contraindicated in patients receiving fluconazole.. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.) WARNINGS (1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress. (4) Use in Pregnancy: There are no adequate and well-controlled studies of DIFLUCAN in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus (See PRECAUTIONS, Pregnancy.) PRECAUTIONS General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided. Fluconazole should be administered with caution to patients with renal dysfunction. Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored. DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur. Single Dose The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Voriconazole Tacrolimus Short-acting benzodiazepines Triazolam Oral Contraceptives Pimozide Hydrochlorothiazide Alfentanil Amitriptyline, nortriptyline Amphotericin B Azithromycin Carbamazepine Calcium Channel Blockers Celecoxib Cyclophosphamide Fentanyl Halofantrine HMG-CoA reductase inhibitors Losartan Methadone Non-steroidal anti-inflammatory drugs Prednisone Saquinavir Sirolimus Vinca Alkaloids Vitamin A Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Zidovudine Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated. . Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20 32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary. Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. . Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated. Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics. Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S (+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary. Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements. Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur. Carcinogenesis, Mutagenesis, and Impairment of Fertility Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda disturbances in parturition were reflected by a slight increase in the number of still born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.) Pregnancy Teratogenic Effects.Pregnancy Category C: Single 150 mg tablet use for Vaginal Candidiasis: There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. Pregnancy Category D: All other indications: A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy.) Human Data Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated with low dose exposure to fluconazole in pregnancy (most subjects received a single oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies. Animal Data Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed. In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations. Caution should be exercised when DIFLUCAN is administered to a nursing woman. Pediatric Use An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.) The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.) Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN. Geriatric Use In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS DIFLUCAN is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during post-marketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Body as a Whole: Asthenia, fatigue, fever, malaise. Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.) Central Nervous System: Seizures, dizziness. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. Other Senses: Taste perversion. Musculoskeletal System: myalgia. Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS), alopecia. Adverse Reactions in Children: The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 OVERDOSAGE There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%. In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Prophylaxis in patients undergoing bone marrow transplantation: The recommended DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children: The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12* mg/kg 400 mg * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) >50 ≤50 (no dialysis) Regular dialysis Percent of Recommended Dose 100% 50% 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140 – age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for intravenous administration using sterile equipment. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. DO NOT ADD SUPPLEMENTARY MEDICATION. Preparation for Administration: 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. HOW SUPPLIED DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN Tablets are supplied as follows: DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG” on the back. NDC 0049-3410-30 Bottles of 30 Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and “ROERIG” on the back. NDC 0049-3420-30 Bottles of 30 NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and “ROERIG” on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and “ROERIG” on the back. NDC 0049-3430-30 Bottles of 30 NDC 0049-3430-41 Unit dose package of 100 Storage: Store tablets below 86°F (30°C). DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottle NDC 0049-3450-19 Fluconazole 1400 mg per bottle Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or 200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose diluents. DIFLUCAN Injections in Glass Bottles: NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIFLUCAN Injections in Viaflex® Plus Plastic Containers: NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6 NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6 NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6 NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6 Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does not adversely affect the product. Protect from freezing. REFERENCES 1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI Document M27-A3, (ISBN 1-56238-666-2), CLSI, 940 West Valley Road, Suite 1400, Wayne, PA,19087-1898 USA, 2008 2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guideline-Second Edition. CLSI Document M44-A2, (ISBN 1-56238-703-0), CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087-1898 USA, 2009 3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of Clinical Microbiology. 45:70–75. company logo LAB-0099-15.0 Revised November 2011 Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION DIFLUCAN® (fluconazole tablets) This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not meant to take the place of your doctor's instructions. Read this information carefully before you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about DIFLUCAN. What Is DIFLUCAN? DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the yeast infection goes away. DIFLUCAN is different from other treatments for vaginal yeast infections because it is a tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet is only about using DIFLUCAN for vaginal yeast infections. For information about using DIFLUCAN for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information about vaginal yeast infections. What Is a Vaginal Yeast Infection? It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are common. About three out of every four adult women will have at least one vaginal yeast infection during their life. Some medicines and medical conditions can increase your chance of getting a yeast infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast infections more often than other women. Personal hygiene and certain types of clothing may increase your chances of getting a yeast infection. Ask your doctor for tips on what you can do to help prevent vaginal yeast infections. If you get a vaginal yeast infection, you may have any of the following symptoms: • itching • a burning feeling when you urinate • redness • soreness • a thick white vaginal discharge that looks like cottage cheese What To Tell Your Doctor Before You Start DIFLUCAN? Do not take Diflucan if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including: Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • diabetes medicines such as glyburide, tolbutamide, glipizide • blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine or felodipine • blood thinners such as warfarin • cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants) • rifampin or rifabutin for tuberculosis • astemizole for allergies • phenytoin or carbamazepine to control seizures • theophylline to control asthma • cisapride for heartburn • quinidine (used to correct disturbances in heart rhythm) • amitriptyline or nortriptyline for depression • pimozide for psychiatric illness • amphotericin B or voriconazole for fungal infections • erythromycin for bacterial infections • cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of cancer • fentanyl, afentanil or methadone for chronic pain • halofantrine for malaria • lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin • non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen • prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory disorders • antiviral medications used to treat HIV like saquinavir or zidovudine • vitamin A nutritional supplement Since there are many brand names for these medicines, check with your doctor or pharmacist if you have any questions. • are taking any over-the-counter medicines you can buy without a prescription, including natural or herbal remedies • have any liver problems. • have any other medical conditions • are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether DIFLUCAN is right for you. • are breast-feeding. DIFLUCAN can pass through breast milk to the baby. • are allergic to any other medicines including those used to treat yeast and other fungal infections. • are allergic to any of the ingredients in DIFLUCAN. The main ingredient of DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist. Who Should Not Take DIFLUCAN? To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking erythromycin, astemizole, pimozide, quinidine, and cisapride (Propulsid®) since it can cause changes in heartbeat in some people if taken with DIFLUCAN. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How Should I Take DIFLUCAN Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time of the day. DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms start to go away after 24 hours. However, it may take several days for your symptoms to go away completely. If there is no change in your symptoms after a few days, call your doctor. Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection. What Should I Avoid while Taking DIFLUCAN? Some medicines can affect how well DIFLUCAN works. Check with your doctor before starting any new medicines within seven days of taking DIFLUCAN. What Are the Possible Side Effects of DIFLUCAN? Like all medicines, DIFLUCAN may cause some side effects that are usually mild to moderate. The most common side effects of DIFLUCAN are: • headache • diarrhea • nausea or upset stomach • dizziness • stomach pain • changes in the way food tastes Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs of an allergic reaction can include shortness of breath; coughing; wheezing; fever; chills; throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the body; or skin rash, hives, blisters or skin peeling. Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in patients with serious medical problems. Call your doctor if your skin or eyes become yellow, your urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit or feel like vomiting or if you have severe skin itching. In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin peeling have been reported. Tell your doctor right away if you get a rash while taking DIFLUCAN. DIFLUCAN may cause other less common side effects besides those listed here. If you develop any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor or pharmacist. Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What to Do For an Overdose In case of an accidental overdose, call your doctor right away or go to the nearest emergency room. How to Store DIFLUCAN Keep DIFLUCAN and all medicines out of the reach of children. General Advice about Prescription Medicines Medicines are sometimes prescribed for conditions that are mentioned in patient information leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not give DIFLUCAN to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about DIFLUCAN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about DIFLUCAN that is written for health professionals. You can also visit the DIFLUCAN Internet site at www.diflucan.com. company logo LAB-0380-5.0 Revised June 2011 Reference ID: 3045153 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:44.002033	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019949s055,019950s059,020090s038lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 38}
12,209	s t ruc tur al f or mu la DIFLUCAN® (Fluconazole Tablets) (Fluconazole for Oral Suspension) DESCRIPTION DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13 H12 F2N6O and molecular weight of 306.3. The structural formula is: Fluconazole is a white crystalline solid which is slightly soluble in water and saline. DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. The C max and AUC data from a food-effect study involving administration of DIFLUCAN (fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken without regard to meals. (see DOSAGE AND ADMINISTRATION.) Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL). Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Ratio of Fluconazole Tissue (Fluid)/Plasma Tissue or Fluid Concentration* Cerebrospinal fluid† 0.5-0.9 Saliva 1 Sputum 1 Blister fluid 1 Urine 10 Normal skin 10 Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nails 1 Blister skin 2 Vaginal tissue 1 Vaginal fluid 0.4-0.7 * Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. Pharmacokinetics in Children In children, the following pharmacokinetic data {Mean (%cv)} have been reported: Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) Cmax (µg/mL) Vdss (L/kg) 9 Months 13 years Single-Oral 2 mg/kg 0.40 (38%) N=14 25.0 2.9 (22%) N=16 ___ 9 Months 13 years Single-Oral 8 mg/kg 0.51 (60%) N=15 19.5 9.8 (20%) N=15 ___ 5-15 years Multiple IV 2 mg/kg 0.49 (40%) N=4 17.4 5.5 (25%) N=5 0.722 (36%) N=4 5-15 years Multiple IV 4 mg/kg 0.59 (64%) N=5 15.2 11.4 (44%) N=6 0.729 (33%) N=5 5-15 years Multiple IV 8 mg/kg 0.66 (31%) N=7 17.6 14.1 (22%) N=8 1.069 (37%) N=7 Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics in Elderly A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4 ± 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject’s terminal elimination half-life versus creatinine clearance compared with the predicted half-life – creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life – creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly. Drug Interaction Studies Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%) and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased 19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers. Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of fluconazole. Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31% (range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10 to –50%). Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.) Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response. Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.) Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased 60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.) Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2. Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17% (range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See PRECAUTIONS.) Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.) Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS and PRECAUTIONS.) Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See PRECAUTIONS.) Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.) Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean ± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.) Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean ± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19% (range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS.) Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See PRECAUTIONS.) Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.) Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.) Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (See PRECAUTIONS.) Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes. Concurrent administration of oral Voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 h of the last dose of fluconazole. (See PRECAUTIONS) Tofacitinib: Co-administration of fluconazole (400 mg on Day 1 and 200 mg once daily for 6 days [Days 2-7]) and tofacitinib (30 mg single dose on Day 5) in healthy subjects resulted in increased mean tofacitinib AUC and Cmax values of approximately 79% (90% CI: 64% – 96%) and 27% (90% CI: 12% – 44%), respectively, compared to administration of tofacitinib alone. (See PRECAUTIONS) Microbiology Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Drug Resistance Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms. Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles. Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 µg/mL), the highest fluconazole dose is recommended. Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Activity In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections. Candida albicans Candida glabrata (Many strains are intermediately susceptible)* Candida parapsilosis Candida tropicalis Cryptococcus neoformans * In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint (≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative therapy is recommended. The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. Candida dubliniensis Candida guilliermondii Candida kefyr Candida lusitaniae Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Susceptibility Testing Methods Cryptococcus neoformans and filamentous fungi: No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi. Candida species: Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1. Table 1: Susceptibility Interpretive Criteria for Fluconazole against Candida species Broth Dilution at 48 hours (MIC in µg/mL) Disk Diffusion at 24 hours (Zone Diameters in mm) Antifungal agent Susceptible (S) Intermediate (I) Resistant (R) Susceptible (S) Intermediate (I) Resistant (R) Fluconazole* ≤ 8.0 16-32 ≥64 ≥19 15-18 ≤14 * Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale. ** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole. A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results QC Strain Macrodilution (MIC in µg/mL) @ 48 hours Microdilution (MIC in µg/mL) @ 48 hours Disk Diffusion (Zone Diameter in mm) @ 24 hours Candida parapsilosis ATCC 22019 2.0-8.0 1.0-4.0 22-33 Candida krusei ATCC 6258 16-64 16-128 ---* Candida albicans ATCC 90028 ---* ---* 28-39 Candida tropicalis ATCC 750 ---* ---* 26-37 ---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. INDICATIONS AND USAGE DIFLUCAN (fluconazole) is indicated for the treatment of: 1. Vaginal candidiasis (vaginal yeast infections due to Candida). 2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL STUDIES Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83-9.) Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation. The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group. Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days Enrolled 448 422 Evaluable at Late Follow-up 347 (77%) 327 (77%) Clinical cure 239/347 (69%) 235/327 (72%) Mycologic eradication 213/347 (61%) 196/327 (60%) Therapeutic cure 190/347 (55%) 179/327 (55%) Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred. Parameter Fluconazole PO Vaginal Products Evaluable patients 448 422 With any adverse event 141 (31%) 112 (27%) Nervous System 90 (20%) 69 (16%) Gastrointestinal 73 (16%) 18 (4%) With drug-related event 117 (26%) 67 (16%) Nervous System 61 (14%) 29 (7%) Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Headache 58 (13%) 28 (7%) Gastrointestinal 68 (15%) 13 (3%) Abdominal pain 25 (6%) 7 (2%) Nausea 30 (7%) 3 (1%) Diarrhea 12 (3%) 2 (<1%) Application site event 0 (0%) 19 (5%) Taste Perversion 6 (1%) 0 (0%) Pediatric Studies Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and mycological response rates were higher in the children treated with fluconazole. Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients. Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication* 55/72 (76%) 6/54 (11%) * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response. The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23% for nystatin. CONTRAINDICATIONS DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole.. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.) Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS (1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Exfoliative skin disorders during treatment with DIFLUCAN have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole. (4) Use in Pregnancy: There are no adequate and well-controlled studies of DIFLUCAN in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus (See PRECAUTIONS, Pregnancy.) PRECAUTIONS General Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions. Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided. Fluconazole should be administered with caution to patients with renal dysfunction. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored. DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur. Single Dose The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19, and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Voriconazole Tacrolimus Short-acting benzodiazepines Tofacitinib Triazolam Oral Contraceptives Pimozide Quinidine Hydrochlorothiazide Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Alfentanil Amitriptyline, nortriptyline Amphotericin B Azithromycin Carbamazepine Calcium Channel Blockers Celecoxib Cyclophosphamide Fentanyl Halofantrine HMG-CoA reductase inhibitors Losartan Methadone Non-steroidal anti-inflammatory drugs Prednisone Saquinavir Sirolimus Vinca Alkaloids Vitamin A Zidovudine Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Cyclosporine: DIFLUCAN significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies). This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated. . Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tofacitinib: Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole, a combined moderate CYP3A4 and potent CYP2C19 inhibitor. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the XELJANZ® [tofacitinib] label). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Triazolam: Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20-32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary. Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive. Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated. Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS.) Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics. Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5 nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Calcium Channel Blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S (+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed. Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued. Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary. Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements. Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur. Carcinogenesis, Mutagenesis, and Impairment of Fertility Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY.) Pregnancy Teratogenic Effects.Pregnancy Category C: Single 150 mg tablet use for Vaginal Candidiasis: There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. Pregnancy Category D: All other indications: A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy.) Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Human Data Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated with low dose exposure to fluconazole in pregnancy (most subjects received a single oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies. Animal Data Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed. In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations. Caution should be exercised when DIFLUCAN is administered to a nursing woman. Pediatric Use An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES.) The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS.) Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN. Geriatric Use In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS DIFLUCAN is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. In Patients Receiving Multiple Doses for Other Infections: Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during post-marketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Body as a Whole: Asthenia, fatigue, fever, malaise. Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.) Central Nervous System: Seizures, dizziness. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. Other Senses: Taste perversion. Musculoskeletal System: myalgia. Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo. Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS), alopecia. Adverse Reactions in Children: The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 OVERDOSAGE There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior. In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma levels by approximately 50%. In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions. DOSAGE AND ADMINISTRATION Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children: The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12* mg/kg 400 mg * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance. These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140 – age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration DIFLUCAN is administered orally. DIFLUCAN can be taken with or without food. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. HOW SUPPLIED DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval shaped, packaged in a single dose unit blister. DIFLUCAN Tablets are supplied as follows: DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG” on the back. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 0049-3410-30 Bottles of 30 DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and “ROERIG” on the back. NDC 0049-3420-30 Bottles of 30 NDC 0049-3420-41 Unit dose package of 100 DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and “ROERIG” on the back. NDC 0049-3500-79 Unit dose package of 1 DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and “ROERIG” on the back. NDC 0049-3430-30 Bottles of 30 NDC 0049-3430-41 Unit dose package of 100 Storage: Store tablets below 86°F (30°C). DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an orange-flavored powder to provide 35 mL per bottle as follows: NDC 0049-3440-19 Fluconazole 350 mg per bottle NDC 0049-3450-19 Fluconazole 1400 mg per bottle Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI Document M27-A3, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, PA,19087, USA, 2008. 2. Clinical and Laboratory Standards Institute (CLSI). Methods for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guideline-Second Edition. CLSI Document M44-A2, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, USA, 2009. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0099-20.2 Revised October 2014 Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION DIFLUCAN (fluconazole tablets) This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not meant to take the place of your doctor's instructions. Read this information carefully before you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about DIFLUCAN. What Is DIFLUCAN? DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the yeast infection goes away. DIFLUCAN is different from other treatments for vaginal yeast infections because it is a tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet is only about using DIFLUCAN for vaginal yeast infections. For information about using DIFLUCAN for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information about vaginal yeast infections. What Is a Vaginal Yeast Infection? It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are common. About three out of every four adult women will have at least one vaginal yeast infection during their life. Some medicines and medical conditions can increase your chance of getting a yeast infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast infections more often than other women. Personal hygiene and certain types of clothing may increase your chances of getting a yeast infection. Ask your doctor for tips on what you can do to help prevent vaginal yeast infections. If you get a vaginal yeast infection, you may have any of the following symptoms: • itching • a burning feeling when you urinate • redness • soreness • a thick white vaginal discharge that looks like cottage cheese What To Tell Your Doctor Before You Start DIFLUCAN? Do not take Diflucan if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including: Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • diabetes medicines such as glyburide, tolbutamide, glipizide • blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine or felodipine • blood thinners such as warfarin • cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants) • rifampin or rifabutin for tuberculosis • astemizole for allergies • phenytoin or carbamazepine to control seizures • theophylline to control asthma • cisapride for heartburn • quinidine (used to correct disturbances in heart rhythm) • amitriptyline or nortriptyline for depression • pimozide for psychiatric illness • amphotericin B or voriconazole for fungal infections • erythromycin for bacterial infections • cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of cancer • fentanyl, afentanil or methadone for chronic pain • halofantrine for malaria • lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin • non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen • prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory disorders • antiviral medications used to treat HIV like saquinavir or zidovudine • tofacitinib for rheumatoid arthritis • vitamin A nutritional supplement Since there are many brand names for these medicines, check with your doctor or pharmacist if you have any questions. • are taking any over-the-counter medicines you can buy without a prescription, including natural or herbal remedies • have any liver problems. • have any other medical conditions • are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether DIFLUCAN is right for you. • are breast-feeding. DIFLUCAN can pass through breast milk to the baby. • are allergic to any other medicines including those used to treat yeast and other fungal infections. • are allergic to any of the ingredients in DIFLUCAN. The main ingredient of DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Who Should Not Take DIFLUCAN? To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking erythromycin, astemizole, pimozide, quinidine, and cisapride (Propulsid®) since it can cause changes in heartbeat in some people if taken with DIFLUCAN. How Should I Take DIFLUCAN Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time of the day. DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms start to go away after 24 hours. However, it may take several days for your symptoms to go away completely. If there is no change in your symptoms after a few days, call your doctor. Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection. What Should I Avoid while Taking DIFLUCAN? Some medicines can affect how well DIFLUCAN works. Check with your doctor before starting any new medicines within seven days of taking DIFLUCAN. What Are the Possible Side Effects of DIFLUCAN? Like all medicines, DIFLUCAN may cause some side effects that are usually mild to moderate. The most common side effects of DIFLUCAN are: • headache • diarrhea • nausea or upset stomach • dizziness • stomach pain • changes in the way food tastes Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs of an allergic reaction can include shortness of breath; coughing; wheezing; fever; chills; throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the body; or skin rash, hives, blisters or skin peeling. Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in patients with serious medical problems. Call your doctor if your skin or eyes become yellow, your urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit or feel like vomiting or if you have severe skin itching. Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin peeling have been reported. Tell your doctor right away if you get a rash while taking DIFLUCAN. DIFLUCAN may cause other less common side effects besides those listed here. If you develop any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor or pharmacist. What to Do For an Overdose In case of an accidental overdose, call your doctor right away or go to the nearest emergency room. How to Store DIFLUCAN Keep DIFLUCAN and all medicines out of the reach of children. General Advice about Prescription Medicines Medicines are sometimes prescribed for conditions that are mentioned in patient information leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not give DIFLUCAN to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about DIFLUCAN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about DIFLUCAN that is written for health professionals. You can also visit the DIFLUCAN Internet site at www.diflucan.com. company logo LAB-0380-6.0 Revised March 2013 Reference ID: 3650838 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:44.054583	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019949s060,020090s044lbl.pdf', 'application_number': 20090, 'submission_type': 'SUPPL ', 'submission_number': 44}
12,213	1 1 2 3 4 5 PV 5324 DPP PROZAC® FLUOXETINE CAPSULES, USP FLUOXETINE ORAL SOLUTION, USP FLUOXETINE DELAYED-RELEASE CAPSULES, USP WARNING 6 Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to 7 placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young 8 adults in short-term studies of major depressive disorder (MDD) and other psychiatric 9 disorders. Anyone considering the use of Prozac or any other antidepressant in a child, 10 adolescent, or young adult must balance this risk with the clinical need. Short-term studies 11 did not show an increase in the risk of suicidality with antidepressants compared to 12 placebo in adults beyond age 24; there was a reduction in risk with antidepressants 13 compared to placebo in adults aged 65 and older. Depression and certain other psychiatric 14 disorders are themselves associated with increases in the risk of suicide. Patients of all ages 15 who are started on antidepressant therapy should be monitored appropriately and 16 observed closely for clinical worsening, suicidality, or unusual changes in behavior. 17 Families and caregivers should be advised of the need for close observation and 18 communication with the prescriber. Prozac is approved for use in pediatric patients with 19 MDD and obsessive compulsive disorder (OCD). (See WARNINGS, Clinical Worsening 20 and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, 21 Pediatric Use.) 22 23 24 25 26 27 28 DESCRIPTION Prozac® (fluoxetine capsules, USP and fluoxetine oral solution, USP) is a psychotropic drug for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α- trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: 29 30 31 32 33 34 35 36 37 38 39 Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg Pulvules also contain FD&C Blue No. 1, and the 40-mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 μmol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Prozac Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 μmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 CLINICAL PHARMACOLOGY Pharmacodynamics The antidepressant, antiobsessive compulsive, and antibulimic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. Absorption, Distribution, Metabolism, and Excretion Systemic bioavailability — In man, following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS). Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical issues related to metabolism/elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use. Variability in metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as 83 84 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. 85 86 87 88 89 90 91 92 93 94 95 96 97 98 Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see Drug Interactions under PRECAUTIONS). Accumulation and slow elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of Prozac. Weekly dosing — Administration of Prozac Weekly once weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of fluoxetine are in the range of the average concentration for 20-mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20-mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared with the once-daily regimen. Cmax for fluoxetine following the 90-mg dose was approximately 1.7-fold higher than the Cmax value for the established 20-mg once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90-mg once-weekly dose and the last 20-mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better to separate the first 90-mg weekly dose and the last 20-mg once-daily dose by 1 week (see 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 DOSAGE AND ADMINISTRATION). Liver disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Renal disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see Use in Patients with Concomitant Illness under PRECAUTIONS and DOSAGE AND ADMINISTRATION). Age Geriatric pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events was observed in those elderly patients. 153 154 155 156 157 158 159 160 161 162 Pediatric pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with major depressive disorder. 163 164 165 166 167 168 169 170 171 172 173 174 175 176 Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. 177 178 179 180 181 CLINICAL TRIALS Major Depressive Disorder Daily Dosing Adult — The efficacy of Prozac for the treatment of patients with major depressive disorder (≥18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg and placebo have shown Prozac 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with major depressive disorder. In these studies, Prozac produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. Prozac was well tolerated and the rate of treatment discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major depressive disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking Prozac compared with those on placebo. Pediatric (children and adolescents) — The efficacy of Prozac 20 mg/day for the treatment of major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo-controlled clinical trials. 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 In both studies independently, Prozac produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Weekly dosing for maintenance/continuation treatment A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded (defined as having a modified HAMD-17 score of ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for major depressive disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once daily. These patients were randomized to double-blind, once-weekly continuation treatment with Prozac Weekly, Prozac 20 mg once daily, or placebo. Prozac Weekly once weekly and Prozac 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. However, the equivalence of these 2 treatments during continuation therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Obsessive Compulsive Disorder 220 Adult — The effectiveness of Prozac for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Prozac Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% 238 239 240 Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD, patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Prozac produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. Bulimia Nervosa The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Prozac or placebo in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, Prozac 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 and persisted throughout each study. The Prozac-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between Prozac 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with Prozac 60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued Prozac 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. Panic Disorder The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. Study 1 (N=180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N=214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. INDICATIONS AND USAGE Major Depressive Disorder Prozac is indicated for the treatment of major depressive disorder. Adult — The efficacy of Prozac was established in 5- and 6-week trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of major depressive disorder (see 295 296 297 298 299 300 301 302 303 304 CLINICAL TRIALS). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The effects of Prozac in hospitalized depressed patients have not been adequately studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 The efficacy of Prozac 20 mg once daily in maintaining a response in major depressive disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in a placebo-controlled trial. 305 306 307 308 309 310 311 312 313 The efficacy of Prozac Weekly once weekly in maintaining a response in major depressive disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks following open-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basis provides the same level of protection from relapse as that provided by Prozac 20 mg daily (see CLINICAL TRIALS). Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see 314 315 316 317 318 319 320 CLINICAL TRIALS). The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should be reevaluated periodically. Obsessive Compulsive Disorder Adult — Prozac is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. 321 322 323 324 325 326 327 328 329 330 331 332 333 334 The efficacy of Prozac was established in 13-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see CLINICAL TRIALS). OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. The effectiveness of Prozac in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in DSM-IV (see 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 CLINICAL TRIALS). Bulimia Nervosa Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa. The efficacy of Prozac was established in 8- to 16-week trials for adult outpatients with moderate to severe bulimia nervosa, i.e., at least 3 bulimic episodes per week for 6 months (see CLINICAL TRIALS). The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Panic Disorder 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of Prozac was established in two 12-week clinical trials in patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL TRIALS). Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 or more of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes. The effectiveness of Prozac in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Prozac is contraindicated in patients known to be hypersensitive to it. Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY)] should be allowed after stopping Prozac before starting an MAOI. Pimozide — Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS). Thioridazine — Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued (see WARNINGS). WARNINGS Clinical Worsening and Suicide Risk — Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Prozac, for a description of the risks of discontinuation of Prozac). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Prozac should be written for the smallest quantity of capsules, or liquid consistent with good patient management, in order to reduce the risk of overdose. It should be noted that Prozac is approved in the pediatric population only for major depressive disorder and obsessive compulsive disorder. Screening Patients for Bipolar Disorder — A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Prozac is not approved for use in treating bipolar depression. Rash and Possibly Allergic Events — In US fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of Prozac, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac should be discontinued. Serotonin Syndrome — The development of a potentially life-threatening serotonin syndrome may occur with SNRIs and SSRIs, including Prozac treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Prozac with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and Drug Interactions under PRECAUTIONS). If concomitant treatment Prozac with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Drug Interactions under PRECAUTIONS). The concomitant use of Prozac with serotonin precursors (such as tryptophan) is not recommended (see Drug Interactions under PRECAUTIONS). Potential Interaction with Thioridazine — In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS). Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS). PRECAUTIONS General Abnormal Bleeding — Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 be cautioned regarding the risk of bleeding associated with the concomitant use of Prozac with NSAIDs, aspirin, or other drugs that affect coagulation. 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 Anxiety and Insomnia — In US placebo-controlled clinical trials for major depressive disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Prozac and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Prozac 60 mg and in 9% and 5% of patients treated with placebo. Among the most common adverse events associated with discontinuation (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in major depressive disorder) (see Table 4). Altered Appetite and Weight — Significant weight loss, especially in underweight depressed or bulimic patients may be an undesirable result of treatment with Prozac. In US placebo-controlled clinical trials for major depressive disorder, 11% of patients treated with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Prozac because of anorexia or weight loss (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Prozac because of anorexia (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Prozac 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. Activation of Mania/Hypomania — In US placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of major depressive disorder (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Prozac and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also Pediatric Use under PRECAUTIONS). Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when Prozac was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted. In two 6-week controlled studies in patients ≥60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration was 129 mmol/L. The observed decreases were not clinically significant. 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 Seizures — In US placebo-controlled clinical trials for major depressive disorder, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patients treated with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of major depressive disorder. Prozac should be introduced with care in patients with a history of seizures. The Long Elimination Half-Lives of Fluoxetine and its Metabolites — Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Use in Patients with Concomitant Illness — Clinical experience with Prozac in patients with concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received Prozac in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis. Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (see Renal disease under CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE AND ADMINISTRATION). In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred during therapy with Prozac, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with Prozac is instituted or discontinued. Interference with Cognitive and Motor Performance — Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Discontinuation of Treatment with Prozac — During marketing of Prozac and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Prozac. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 DOSAGE AND ADMINISTRATION). Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Prozac and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Prozac. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Prozac. Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Prozac and triptans, tramadol or other serotonergic agents. Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected. Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs, or alcohol. Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Patients should be advised to notify their physician if they are breast-feeding an infant. 661 662 663 664 665 666 667 668 Patients should be advised to notify their physician if they develop a rash or hives. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 CONTRAINDICATIONS and WARNINGS). Drugs metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. 685 686 687 688 689 690 691 CNS active drugs — The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see 692 693 694 695 696 697 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. 698 699 700 Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT 701 702 703 704 705 706 c prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 concurrent use of pimozide and Prozac. Concomitant use of Prozac and pimozide is contraindicated (see 707 708 709 CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS and WARNINGS. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients (see 710 711 712 713 714 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. 715 716 717 718 Tryptophan — Five patients receiving Prozac in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. 719 720 Monoamine oxidase inhibitors — See CONTRAINDICATIONS. 721 Other drugs effective in the treatment of major depressive disorder — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see 722 723 724 725 726 727 728 Accumulation and slow elimination under CLINICAL PHARMACOLOGY, and Drugs metabolized by CYP2D6 under Drug Interactions). Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including Prozac, and the potential for serotonin syndrome, caution is advised when Prozac is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see 729 730 731 732 733 734 Serotonin Syndrome under WARNINGS). The concomitant use of Prozac with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Prozac with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see 735 736 737 738 Serotonin Syndrome under WARNINGS). Potential effects of coadministration of drugs tightly bound to plasma proteins — Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs (see 739 740 741 742 743 744 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.) — Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluoxetine. 745 746 747 748 749 750 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Warfarin — Altered anticoagulant effects, including increased bleeding, have been reported when fluoxetine is coadministered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. 751 752 753 Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 754 755 756 757 758 759 760 Carcinogenesis, Mutagenesis, Impairment of Fertility There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) was not observed. Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m 761 762 763 764 2 basis], produced no evidence of carcinogenicity. Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. 765 766 767 768 Impairment of fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 2 basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use). Pregnancy Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects — Neonates exposed to Prozac and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Monoamine oxidase inhibitors under CONTRAINDICATIONS). Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 When treating a pregnant woman with Prozac during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Labor and Delivery The effect of Prozac on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. Pediatric Use The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 (see CLINICAL TRIALS). The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see CLINICAL TRIALS). The safety and effectiveness in pediatric patients <8 years of age in major depressive disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major depressive disorder or OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY). The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS). Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. (See WARNINGS, Clinical Worsening and Suicide Risk.) Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain. Prozac is approved for use in pediatric patients with MDD and OCD (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Prozac in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use US fluoxetine clinical trials as of May 8, 1995 (10,782 patients) included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established (see CLINICAL TRIALS). For pharmacokinetic information in geriatric patients, see Age under CLINICAL PHARMACOLOGY. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other SSRIs, fluoxetine has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS). ADVERSE REACTIONS Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled 926 clinical trials (excluding data from extensions of trials) — Table 2 enumerates the most common treatment-emergent adverse events associated with the use of Prozac (incidence of at least 5% for Prozac and at least twice that for placebo within at least 1 of the indications) for the treatment of major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder in US plus non-US controlled trials. Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who participated in US major depressive disorder, OCD, and bulimia controlled clinical trials and US 927 928 929 930 931 932 933 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 plus non-US panic disorder controlled clinical trials. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2. 934 935 936 937 938 939 Table 2: Most Common Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Event Prozac (N=1728) Placebo (N=975) Prozac (N=266) Placebo (N=89) Prozac (N=450) Placebo (N=267) Prozac (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence2 2 -- -- -- 7 -- 1 -- Abnormal ejaculation2 -- -- 7 -- 7 -- 2 1 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. 940 941 942 943 944 945 946 2 Denominator used was for males only (N=690 Prozac major depressive disorder; N=410 placebo major depressive disorder; N=116 Prozac OCD; N=43 placebo OCD; N=14 Prozac bulimia; N=1 placebo bulimia; N=162 Prozac panic; N=121 placebo panic). -- Incidence less than 1%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Table 3: Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 947 948 1 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Event2 Prozac (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. 949 950 951 952 953 954 955 956 2 Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an incidence on placebo ≥ Prozac (major depressive disorder, OCD, bulimia, and panic disorder combined): abdominal pain, abnormal dreams, accidental injury, back pain, cough increased, major depressive disorder (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis. -- Incidence less than 1%. Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic 957 disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 4 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. 958 959 960 961 962 963 964 965 966 Table 4: Most Common Adverse Events Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- 1 Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. 967 968 969 Other adverse events in pediatric patients (children and adolescents) — Treatment-emergent adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult studies, as shown in Tables 2 and 3. However, the following adverse events (excluding those which appear in the body or footnotes of Tables 2 and 3 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. 970 971 972 973 974 975 976 977 978 979 980 981 982 The most common adverse event (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event associated with discontinuation was collected. Events observed in Prozac Weekly clinical trials — Treatment-emergent adverse events in clinical trials with Prozac Weekly were similar to the adverse events reported by patients in clinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking Prozac Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking Prozac 20 mg daily (10% versus 5%, respectively). 983 984 985 986 987 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US major depressive disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Events Observed in Clinical Trials Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient treated with Prozac and which did not have a substantial probability of being acutely life-threatening. Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. Body as a Whole — Frequent: chest pain, chills; Infrequent: chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome1, photosensitivity reaction. Cardiovascular System — Frequent: hemorrhage, hypertension, palpitation; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System — Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional — Frequent: weight gain; Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis. Nervous System — Frequent: agitation, amnesia, confusion, emotional lability, sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder2, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor. Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor. Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System — Frequent: urinary frequency; Infrequent: abortion3, albuminuria, amenorrhea3, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation3, fibrocystic breast3, hematuria, leukorrhea3, menorrhagia3, metrorrhagia3, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage3; Rare: breast engorgement, glycosuria, hypomenorrhea3, kidney pain, oliguria, priapism3, uterine hemorrhage3, uterine fibroids enlarged3. 1 Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. 2 Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. 3 Adjusted for gender. Postintroduction Reports Voluntary reports of adverse events temporally associated with Prozac that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors. 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 DRUG ABUSE AND DEPENDENCE Controlled substance class — Prozac is not a controlled substance. Physical and psychological dependence — Prozac has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope. 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management of Overdose). Management of Overdose Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS). Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 DOSAGE AND ADMINISTRATION 1168 1169 1170 Major Depressive Disorder Initial Treatment Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. 1171 1172 1173 1174 1175 1176 1177 1178 A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients were administered fluoxetine doses of 10 to 20 mg/day (see 1179 1180 1181 1182 1183 1184 1185 1186 CLINICAL TRIALS). Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All patients — As with other drugs effective in the treatment of major depressive disorder, the full effect may be delayed until 4 weeks of treatment or longer. 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Daily Dosing Systematic evaluation of Prozac in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day (see CLINICAL TRIALS). Weekly Dosing Systematic evaluation of Prozac Weekly in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with Prozac 20 mg once daily. However, therapeutic equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mg given daily for delaying time to relapse has not been established (see CLINICAL TRIALS). Weekly dosing with Prozac Weekly capsules is recommended to be initiated 7 days after the last daily dose of Prozac 20 mg (see Weekly dosing under CLINICAL PHARMACOLOGY). If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily dosing regimen (see CLINICAL TRIALS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Switching Patients to a Tricyclic Antidepressant (TCA) 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS, Drug Interactions). Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping Prozac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS). Obsessive Compulsive Disorder Initial Treatment Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo (see 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 CLINICAL TRIALS). In 1 of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once-a-day (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 CLINICAL TRIALS). In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. All patients — As with the use of Prozac in the treatment of major depressive disorder, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment While there are no systematic studies that answer the question of how long to continue Prozac, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of Prozac after 13 weeks has not been documented in controlled trials, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 Bulimia Nervosa Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo (see CLINICAL TRIALS). Only the 60-mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking Prozac 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment (see CLINICAL TRIALS). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Panic Disorder Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see CLINICAL TRIALS). Treatment should be initiated with a dose of 10 mg/day. After 1 week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic disorder. As with the use of Prozac in other indications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 Maintenance/Continuation Treatment 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 While there are no systematic studies that answer the question of how long to continue Prozac, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Prozac and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Prozac during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Prozac in the third trimester. Discontinuation of Treatment with Prozac Symptoms associated with discontinuation of Prozac and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. HOW SUPPLIED The following products are manufactured by Eli Lilly and Company for Dista Products Company. Prozac® Pulvules®, USP, are available in: The 10-mg1, Pulvule is opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body: NDC 0777-3104-02 (PU31042) - Bottles of 100 The 20-mg1 Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body: NDC 0777-3105-30 (PU31052) - Bottles of 30 NDC 0777-3105-02 (PU31052) - Bottles of 100 NDC 0777-3105-07 (PU31052) - Bottles of 2000 The 40-mg1 Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU31072) - Bottles of 30 The following is manufactured by OSG Norwich Pharmaceuticals, Inc., North Norwich, NY, 13814, for Dista Products Company: Liquid, Oral Solution is available in: 20 mg1 per 5 mL with mint flavor: NDC 0777-5120-58 (MS-51203) - Bottles of 120 mL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 The following product is manufactured and distributed by Eli Lilly and Company: Prozac® Weekly™ Capsules are available in: The 90-mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) - Blister package of 4 ______________________ 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1 Fluoxetine base equivalent. 2 Protect from light. 3 Dispense in a tight, light-resistant container. Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). ANIMAL TOXICOLOGY Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. Literature revised June 21, 2007 Eli Lilly and Company Indianapolis, IN 46285, USA www.lilly.com PV 5324 DPP PRINTED IN USA 1341 Medication Guide 1342 Antidepressant Medicines, Depression and other Serious Mental 1343 Illnesses, and Suicidal Thoughts or Actions 1344 1345 1346 1347 1348 1349 1350 Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant 1351 medicines, depression and other serious mental illnesses, and suicidal thoughts 1352 or actions? 1353 1354 1355 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? 1385 1386 1387 1388 1389 1390 1391 • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:44.484531	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018936s081s082,020101s037,021235s009lbl.pdf', 'application_number': 20101, 'submission_type': 'SUPPL ', 'submission_number': 37}
12,214	1 PV 5326 DPP 1 PROZAC® 2 FLUOXETINE CAPSULES, USP 3 FLUOXETINE ORAL SOLUTION, USP 4 FLUOXETINE DELAYED-RELEASE CAPSULES, USP 5 WARNING 6 Suicidality and Antidepressant Drugs — Antidepressants increased the risk compared to 7 placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young 8 adults in short-term studies of major depressive disorder (MDD) and other psychiatric 9 disorders. Anyone considering the use of Prozac or any other antidepressant in a child, 10 adolescent, or young adult must balance this risk with the clinical need. Short-term studies 11 did not show an increase in the risk of suicidality with antidepressants compared to 12 placebo in adults beyond age 24; there was a reduction in risk with antidepressants 13 compared to placebo in adults aged 65 and older. Depression and certain other psychiatric 14 disorders are themselves associated with increases in the risk of suicide. Patients of all ages 15 who are started on antidepressant therapy should be monitored appropriately and 16 observed closely for clinical worsening, suicidality, or unusual changes in behavior. 17 Families and caregivers should be advised of the need for close observation and 18 communication with the prescriber. Prozac is approved for use in pediatric patients with 19 MDD and obsessive compulsive disorder (OCD). (See WARNINGS, Clinical Worsening 20 and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, 21 Pediatric Use.) 22 DESCRIPTION 23 Prozac® (fluoxetine capsules, USP and fluoxetine oral solution, USP) is a psychotropic drug 24 for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder 25 (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α- 26 trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of 27 C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is: 28 29 Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL 30 in water. 31 Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 32 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also contain starch, 33 gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg 34 Pulvules also contain FD&C Blue No. 1, and the 40-mg Pulvule also contains FD&C Blue No. 1 35 and FD&C Yellow No. 6. 36 The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 μmol) of 37 fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, 38 and sucrose. 39 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Prozac Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of 40 fluoxetine hydrochloride equivalent to 90 mg (291 μmol) of fluoxetine. The capsules also 41 contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hypromellose acetate 42 succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, 43 and other inactive ingredients. 44 CLINICAL PHARMACOLOGY 45 Pharmacodynamics 46 The antidepressant, antiobsessive compulsive, and antibulimic actions of fluoxetine are 47 presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically 48 relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into 49 human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake 50 inhibitor of serotonin than of norepinephrine. 51 Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized 52 to be associated with various anticholinergic, sedative, and cardiovascular effects of classical 53 tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors 54 from brain tissue much less potently in vitro than do the tricyclic drugs. 55 Absorption, Distribution, Metabolism, and Excretion 56 Systemic bioavailability — In man, following a single oral 40-mg dose, peak plasma 57 concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. 58 The Pulvule, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are 59 bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although 60 it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, 61 fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed-release 62 formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the 63 gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of 64 absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. 65 Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 66 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and 67 α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has 68 not been fully evaluated, but may be important (see PRECAUTIONS). 69 Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine 70 enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake 71 inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is 72 eliminated more slowly and is the predominant enantiomer present in plasma at steady state. 73 Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a 74 number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is 75 formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and 76 selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or 77 S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of 78 serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive 79 metabolites excreted by the kidney. 80 Clinical issues related to metabolism/elimination — The complexity of the metabolism of 81 fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use. 82 Variability in metabolism — A subset (about 7%) of the population has reduced activity of the 83 drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as 84 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study 85 involving labeled and unlabeled enantiomers administered as a racemate, these individuals 86 metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of 87 S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The 88 metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with 89 normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active 90 enantiomers was not significantly greater among poor metabolizers. Thus, the net 91 pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways 92 (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine 93 achieves a steady-state concentration rather than increasing without limit. 94 Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs 95 and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, 96 concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may 97 lead to drug interactions (see Drug Interactions under PRECAUTIONS). 98 Accumulation and slow elimination — The relatively slow elimination of fluoxetine 99 (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic 100 administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after 101 acute and chronic administration), leads to significant accumulation of these active species in 102 chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days 103 of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and 104 norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of 105 fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s 106 metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear 107 pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple 108 dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 109 weeks. 110 The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing 111 is stopped, active drug substance will persist in the body for weeks (primarily depending on 112 individual patient characteristics, previous dosing regimen, and length of previous therapy at 113 discontinuation). This is of potential consequence when drug discontinuation is required or when 114 drugs are prescribed that might interact with fluoxetine and norfluoxetine following the 115 discontinuation of Prozac. 116 Weekly dosing — Administration of Prozac Weekly once weekly results in increased 117 fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared 118 with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 119 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of 120 clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of 121 fluoxetine are in the range of the average concentration for 20-mg once-daily dosing. Average 122 trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the 123 concentrations maintained by 20-mg once-daily dosing. Average steady-state concentrations of 124 either once-daily or once-weekly dosing are in relative proportion to the total dose administered. 125 Average steady-state fluoxetine concentrations are approximately 50% lower following the 126 once-weekly regimen compared with the once-daily regimen. 127 Cmax for fluoxetine following the 90-mg dose was approximately 1.7-fold higher than the Cmax 128 value for the established 20-mg once-daily regimen following transition the next day to the 129 once-weekly regimen. In contrast, when the first 90-mg once-weekly dose and the last 20-mg 130 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient 131 increase in the average steady-state concentrations of fluoxetine observed following transition 132 the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better 133 to separate the first 90-mg weekly dose and the last 20-mg once-daily dose by 1 week (see 134 DOSAGE AND ADMINISTRATION). 135 Liver disease — As might be predicted from its primary site of metabolism, liver impairment 136 can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in 137 a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen 138 in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean 139 duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal 140 subjects. This suggests that the use of fluoxetine in patients with liver disease must be 141 approached with caution. If fluoxetine is administered to patients with liver disease, a lower or 142 less frequent dose should be used (see PRECAUTIONS and DOSAGE AND 143 ADMINISTRATION). 144 Renal disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg 145 once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma 146 concentrations comparable with those seen in patients with normal renal function. While the 147 possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels 148 in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely 149 necessary in renally impaired patients (see Use in Patients with Concomitant Illness under 150 PRECAUTIONS and DOSAGE AND ADMINISTRATION). 151 Age 152 Geriatric pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly 153 subjects (>65 years of age) did not differ significantly from that in younger normal subjects. 154 However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not 155 adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they 156 have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age 157 upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy 158 depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined 159 fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 160 weeks. No unusual age-associated pattern of adverse events was observed in those elderly 161 patients. 162 Pediatric pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were 163 evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) 164 diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine 165 20 mg/day was administered for up to 62 days. The average steady-state concentrations of 166 fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, 167 respectively). The average norfluoxetine steady-state concentrations in these children were 168 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be 169 almost entirely explained by differences in weight. No gender-associated difference in fluoxetine 170 pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma 171 concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed 172 with major depressive disorder. 173 Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in 174 children relative to adults; however, these concentrations were within the range of concentrations 175 observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated 176 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 177 4 weeks of daily dosing. 178 CLINICAL TRIALS 179 Major Depressive Disorder 180 Daily Dosing 181 Adult — The efficacy of Prozac for the treatment of patients with major depressive disorder 182 (≥18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was 183 shown to be significantly more effective than placebo as measured by the Hamilton Depression 184 Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the 185 HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. 186 Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg and placebo 187 have shown Prozac 20 mg daily to be effective in the treatment of elderly patients (≥60 years of 188 age) with major depressive disorder. In these studies, Prozac produced a significantly higher rate 189 of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a 190 total endpoint HAM-D score of ≤8. Prozac was well tolerated and the rate of treatment 191 discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). 192 A study was conducted involving depressed outpatients who had responded (modified 193 HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of 194 major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week 195 open-treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to 196 continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a 197 statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis 198 of major depressive disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was 199 observed for patients taking Prozac compared with those on placebo. 200 Pediatric (children and adolescents) — The efficacy of Prozac 20 mg/day for the treatment of 201 major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to 202 <13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo-controlled 203 clinical trials. 204 In both studies independently, Prozac produced a statistically significantly greater mean 205 change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline 206 to endpoint than did placebo. 207 Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness 208 on the basis of age or gender. 209 Weekly dosing for maintenance/continuation treatment 210 A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for 211 major depressive disorder who had responded (defined as having a modified HAMD-17 score of 212 ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for major depressive disorder) for 213 3 consecutive weeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once 214 daily. These patients were randomized to double-blind, once-weekly continuation treatment with 215 Prozac Weekly, Prozac 20 mg once daily, or placebo. Prozac Weekly once weekly and Prozac 216 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of 217 depressive symptoms) compared with placebo for a period of 25 weeks. However, the 218 equivalence of these 2 treatments during continuation therapy has not been established. 219 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Obsessive Compulsive Disorder 220 Adult — The effectiveness of Prozac for the treatment of obsessive compulsive disorder 221 (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of 222 adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once-a-day 223 schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD 224 (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale 225 (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced 226 mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit 227 reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean 228 reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit 229 reduction for placebo patients. While there was no indication of a dose-response relationship for 230 effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically 231 better responses in the 2 higher dose groups. The following table provides the outcome 232 classification by treatment group on the Clinical Global Impression (CGI) improvement scale for 233 Studies 1 and 2 combined: 234 235 Outcome Classification (%) on CGI Improvement Scale for 236 Completers in Pool of Two OCD Studies 237 Prozac Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% 238 Exploratory analyses for age and gender effects on outcome did not suggest any differential 239 responsiveness on the basis of age or sex. 240 Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients 241 (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD, 242 patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose 243 was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and 244 tolerability. Prozac produced a statistically significantly greater mean change from baseline to 245 endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive 246 Scale (CY-BOCS). 247 Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of 248 age or gender. 249 Bulimia Nervosa 250 The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and 251 one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria 252 for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Prozac or placebo 253 in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a 254 day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median 255 binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, 256 respectively. In these 3 studies, Prozac 60 mg, but not 20 mg, was statistically significantly 257 superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The 258 statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 259 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 and persisted throughout each study. The Prozac-related reduction in bulimic episodes appeared 260 to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. 261 In each of these 3 studies, the treatment effect, as measured by differences between Prozac 262 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at 263 endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for 264 vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in 265 patients with higher baseline frequencies. Although some patients achieved freedom from 266 binge-eating and purging as a result of treatment, for the majority, the benefit was a partial 267 reduction in the frequency of binge-eating and purging. 268 In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging 269 subtype, who had responded during a single-blind, 8-week acute treatment phase with Prozac 270 60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to 52 weeks 271 of observation for relapse. Response during the single-blind phase was defined by having 272 achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during 273 the double-blind phase was defined as a persistent return to baseline vomiting frequency or 274 physician judgment that the patient had relapsed. Patients receiving continued Prozac 60 mg/day 275 experienced a significantly longer time to relapse over the subsequent 52 weeks compared with 276 those receiving placebo. 277 Panic Disorder 278 The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 279 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a 280 primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. 281 Study 1 (N=180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 282 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on 283 the basis of clinical response and tolerability. A statistically significantly greater percentage of 284 Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 285 42% versus 28%, respectively. 286 Study 2 (N=214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 287 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on 288 the basis of clinical response and tolerability. A statistically significantly greater percentage of 289 Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 290 62% versus 44%, respectively. 291 INDICATIONS AND USAGE 292 Major Depressive Disorder 293 Prozac is indicated for the treatment of major depressive disorder. 294 Adult — The efficacy of Prozac was established in 5- and 6-week trials with depressed adult 295 and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the 296 DSM-III (currently DSM-IV) category of major depressive disorder (see CLINICAL TRIALS). 297 A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly 298 every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily 299 functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of 300 interest in usual activities, significant change in weight and/or appetite, insomnia or 301 hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or 302 worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. 303 The effects of Prozac in hospitalized depressed patients have not been adequately studied. 304 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 The efficacy of Prozac 20 mg once daily in maintaining a response in major depressive 305 disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) 306 was demonstrated in a placebo-controlled trial. 307 The efficacy of Prozac Weekly once weekly in maintaining a response in major depressive 308 disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks following 309 open-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 310 weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basis 311 provides the same level of protection from relapse as that provided by Prozac 20 mg daily 312 (see CLINICAL TRIALS). 313 Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was 314 established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose 315 diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive 316 disorder (see CLINICAL TRIALS). 317 The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended 318 periods should be reevaluated periodically. 319 Obsessive Compulsive Disorder 320 Adult — Prozac is indicated for the treatment of obsessions and compulsions in patients with 321 obsessive compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or 322 compulsions cause marked distress, are time-consuming, or significantly interfere with social or 323 occupational functioning. 324 The efficacy of Prozac was established in 13-week trials with obsessive compulsive outpatients 325 whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see CLINICAL 326 TRIALS). 327 OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images 328 (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors 329 (compulsions) that are recognized by the person as excessive or unreasonable. 330 The effectiveness of Prozac in long-term use, i.e., for more than 13 weeks, has not been 331 systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use 332 Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug 333 for the individual patient (see DOSAGE AND ADMINISTRATION). 334 Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was 335 established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in 336 DSM-IV (see CLINICAL TRIALS). 337 Bulimia Nervosa 338 Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with 339 moderate to severe bulimia nervosa. 340 The efficacy of Prozac was established in 8- to 16-week trials for adult outpatients with 341 moderate to severe bulimia nervosa, i.e., at least 3 bulimic episodes per week for 6 months (see 342 CLINICAL TRIALS). 343 The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who 344 responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then 345 observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled 346 trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Prozac for 347 extended periods should periodically reevaluate the long-term usefulness of the drug for the 348 individual patient (see DOSAGE AND ADMINISTRATION). 349 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Panic Disorder 350 Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined 351 in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and 352 associated concern about having additional attacks, worry about the implications or 353 consequences of the attacks, and/or a significant change in behavior related to the attacks. 354 The efficacy of Prozac was established in two 12-week clinical trials in patients whose 355 diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL TRIALS). 356 Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a 357 discrete period of intense fear or discomfort in which 4 or more of the following symptoms 358 develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or 359 accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath 360 or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal 361 distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of 362 dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes. 363 The effectiveness of Prozac in long-term use, i.e., for more than 12 weeks, has not been 364 established in placebo-controlled trials. Therefore, the physician who elects to use Prozac for 365 extended periods should periodically reevaluate the long-term usefulness of the drug for the 366 individual patient (see DOSAGE AND ADMINISTRATION). 367 CONTRAINDICATIONS 368 Prozac is contraindicated in patients known to be hypersensitive to it. 369 Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, 370 reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid 371 fluctuations of vital signs, and mental status changes that include extreme agitation progressing 372 to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase 373 inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started 374 on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. 375 Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 376 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have 377 very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has 378 been prescribed chronically and/or at higher doses (see Accumulation and slow elimination 379 under CLINICAL PHARMACOLOGY)] should be allowed after stopping Prozac before starting 380 an MAOI. 381 Pimozide — Concomitant use in patients taking pimozide is contraindicated (see 382 PRECAUTIONS). 383 Thioridazine — Thioridazine should not be administered with Prozac or within a minimum of 384 5 weeks after Prozac has been discontinued (see WARNINGS). 385 WARNINGS 386 Clinical Worsening and Suicide Risk — Patients with major depressive disorder (MDD), 387 both adult and pediatric, may experience worsening of their depression and/or the emergence of 388 suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they 389 are taking antidepressant medications, and this risk may persist until significant remission 390 occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these 391 disorders themselves are the strongest predictors of suicide. There has been a long-standing 392 concern, however, that antidepressants may have a role in inducing worsening of depression and 393 the emergence of suicidality in certain patients during the early phases of treatment. Pooled 394 analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) 395 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in 396 children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and 397 other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality 398 with antidepressants compared to placebo in adults beyond age 24; there was a reduction with 399 antidepressants compared to placebo in adults aged 65 and older. 400 The pooled analyses of placebo-controlled trials in children and adolescents with MDD, 401 obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 402 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of 403 placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 404 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 405 patients. There was considerable variation in risk of suicidality among drugs, but a tendency 406 toward an increase in the younger patients for almost all drugs studied. There were differences in 407 absolute risk of suicidality across the different indications, with the highest incidence in MDD. 408 The risk differences (drug versus placebo), however, were relatively stable within age strata and 409 across indications. These risk differences (drug-placebo difference in the number of cases of 410 suicidality per 1000 patients treated) are provided in Table 1. 411 412 Table 1 413 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases 414 No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but 415 the number was not sufficient to reach any conclusion about drug effect on suicide. 416 It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several 417 months. However, there is substantial evidence from placebo-controlled maintenance trials in 418 adults with depression that the use of antidepressants can delay the recurrence of depression. 419 All patients being treated with antidepressants for any indication should be monitored 420 appropriately and observed closely for clinical worsening, suicidality, and unusual changes 421 in behavior, especially during the initial few months of a course of drug therapy, or at times 422 of dose changes, either increases or decreases. 423 The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, 424 aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have 425 been reported in adult and pediatric patients being treated with antidepressants for major 426 depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. 427 Although a causal link between the emergence of such symptoms and either the worsening of 428 depression and/or the emergence of suicidal impulses has not been established, there is concern 429 that such symptoms may represent precursors to emerging suicidality. 430 Consideration should be given to changing the therapeutic regimen, including possibly 431 discontinuing the medication, in patients whose depression is persistently worse, or who are 432 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 experiencing emergent suicidality or symptoms that might be precursors to worsening depression 433 or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the 434 patient’s presenting symptoms. 435 If the decision has been made to discontinue treatment, medication should be tapered, as 436 rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with 437 certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, 438 Discontinuation of Treatment with Prozac, for a description of the risks of discontinuation of 439 Prozac). 440 Families and caregivers of patients being treated with antidepressants for major 441 depressive disorder or other indications, both psychiatric and nonpsychiatric, should be 442 alerted about the need to monitor patients for the emergence of agitation, irritability, 443 unusual changes in behavior, and the other symptoms described above, as well as the 444 emergence of suicidality, and to report such symptoms immediately to health care 445 providers. Such monitoring should include daily observation by families and caregivers. 446 Prescriptions for Prozac should be written for the smallest quantity of capsules, or liquid 447 consistent with good patient management, in order to reduce the risk of overdose. 448 It should be noted that Prozac is approved in the pediatric population only for major depressive 449 disorder and obsessive compulsive disorder. 450 Screening Patients for Bipolar Disorder — A major depressive episode may be the initial 451 presentation of bipolar disorder. It is generally believed (though not established in controlled 452 trials) that treating such an episode with an antidepressant alone may increase the likelihood of 453 precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the 454 symptoms described above represent such a conversion is unknown. However, prior to initiating 455 treatment with an antidepressant, patients with depressive symptoms should be adequately 456 screened to determine if they are at risk for bipolar disorder; such screening should include a 457 detailed psychiatric history, including a family history of suicide, bipolar disorder, and 458 depression. It should be noted that Prozac is not approved for use in treating bipolar depression. 459 Rash and Possibly Allergic Events — In US fluoxetine clinical trials as of May 8, 1995, 7% 460 of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash 461 and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from 462 treatment because of the rash and/or systemic signs or symptoms associated with the rash. 463 Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, 464 edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild 465 transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine 466 and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these 467 events were reported to recover completely. 468 In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous 469 systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to 470 have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was 471 considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic 472 syndromes suggestive of serum sickness. 473 Since the introduction of Prozac, systemic events, possibly related to vasculitis and including 474 lupus-like syndrome, have developed in patients with rash. Although these events are rare, they 475 may be serious, involving the lung, kidney, or liver. Death has been reported to occur in 476 association with these systemic events. 477 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria 478 alone and in combination, have been reported. 479 Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, 480 have been reported rarely. These events have occurred with dyspnea as the only preceding 481 symptom. 482 Whether these systemic events and rash have a common underlying cause or are due to 483 different etiologies or pathogenic processes is not known. Furthermore, a specific underlying 484 immunologic basis for these events has not been identified. Upon the appearance of rash or of 485 other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac 486 should be discontinued. 487 Serotonin Syndrome — The development of a potentially life-threatening serotonin syndrome 488 may occur with SNRIs and SSRIs, including Prozac treatment, particularly with concomitant use 489 of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin 490 (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., 491 agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, 492 hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or 493 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). 494 The concomitant use of Prozac with MAOIs intended to treat depression is contraindicated (see 495 CONTRAINDICATIONS and Drug Interactions under PRECAUTIONS). 496 If concomitant treatment Prozac with a 5-hydroxytryptamine receptor agonist (triptan) is 497 clinically warranted, careful observation of the patient is advised, particularly during treatment 498 initiation and dose increases (see Drug Interactions under PRECAUTIONS). 499 The concomitant use of Prozac with serotonin precursors (such as tryptophan) is not 500 recommended (see Drug Interactions under PRECAUTIONS). 501 Potential Interaction with Thioridazine — In a study of 19 healthy male subjects, which 502 included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of 503 thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the 504 slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin 505 hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study 506 suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will 507 produce elevated plasma levels of thioridazine (see PRECAUTIONS). 508 Thioridazine administration produces a dose-related prolongation of the QTc interval, which is 509 associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, 510 and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of 511 thioridazine metabolism (see CONTRAINDICATIONS). 512 PRECAUTIONS 513 General 514 Abnormal Bleeding — SSRIs and SNRIs, including fluoxetine, may increase the risk of 515 bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and 516 other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control 517 and cohort design) have demonstrated an association between use of drugs that interfere with 518 serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to 519 SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to 520 life-threatening hemorrhages. 521 Patients should be cautioned about the risk of bleeding associated with the concomitant use of 522 fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation (see Drug Interactions). 523 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Anxiety and Insomnia — In US placebo-controlled clinical trials for major depressive 524 disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with 525 placebo reported anxiety, nervousness, or insomnia. 526 In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients 527 treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of 528 patients treated with Prozac and in 7% of patients treated with placebo. 529 In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of 530 patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and 531 nervousness were reported, respectively, in 15% and 11% of patients treated with Prozac 60 mg 532 and in 9% and 5% of patients treated with placebo. 533 Among the most common adverse events associated with discontinuation (incidence at least 534 twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event 535 associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety 536 (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% 537 in major depressive disorder) (see Table 4). 538 Altered Appetite and Weight — Significant weight loss, especially in underweight depressed 539 or bulimic patients may be an undesirable result of treatment with Prozac. 540 In US placebo-controlled clinical trials for major depressive disorder, 11% of patients treated 541 with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). 542 Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated 543 with placebo. However, only rarely have patients discontinued treatment with Prozac because of 544 anorexia or weight loss (see also Pediatric Use under PRECAUTIONS). 545 In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% 546 of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued 547 treatment with Prozac because of anorexia (see also Pediatric Use under PRECAUTIONS). 548 In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac 549 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients 550 treated with Prozac 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients 551 treated with placebo in the 16-week double-blind trial. Weight change should be monitored 552 during therapy. 553 Activation of Mania/Hypomania — In US placebo-controlled clinical trials for major 554 depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 555 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a 556 small proportion of patients with Major Affective Disorder treated with other marketed drugs 557 effective in the treatment of major depressive disorder (see also Pediatric Use under 558 PRECAUTIONS). 559 In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of 560 patients treated with Prozac and no patients treated with placebo. No patients reported 561 mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical 562 trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also Pediatric 563 Use under PRECAUTIONS). 564 Hyponatremia — Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, 565 including Prozac. In many cases, this hyponatremia appears to be the result of the syndrome of 566 inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 567 110 mmol/L have been reported and appeared to be reversible when Prozac was discontinued. 568 Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, 569 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 patients taking diuretics or who are otherwise volume depleted may be at greater risk (see 570 Geriatric Use). Discontinuation of Prozac should be considered in patients with symptomatic 571 hyponatremia and appropriate medical intervention should be instituted. 572 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory 573 impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or 574 acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, 575 and death. 576 Seizures — In US placebo-controlled clinical trials for major depressive disorder, convulsions 577 (or events described as possibly having been seizures) were reported in 0.1% of patients treated 578 with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US 579 placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials as of 580 May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar 581 to that associated with other marketed drugs effective in the treatment of major depressive 582 disorder. Prozac should be introduced with care in patients with a history of seizures. 583 The Long Elimination Half-Lives of Fluoxetine and its Metabolites — Because of the long 584 elimination half-lives of the parent drug and its major active metabolite, changes in dose will not 585 be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose 586 and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND 587 ADMINISTRATION). 588 Use in Patients with Concomitant Illness — Clinical experience with Prozac in patients with 589 concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with 590 diseases or conditions that could affect metabolism or hemodynamic responses. 591 Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent 592 history of myocardial infarction or unstable heart disease. Patients with these diagnoses were 593 systematically excluded from clinical studies during the product’s premarket testing. However, 594 the electrocardiograms of 312 patients who received Prozac in double-blind trials were 595 retrospectively evaluated; no conduction abnormalities that resulted in heart block were 596 observed. The mean heart rate was reduced by approximately 3 beats/min. 597 In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, 598 norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A 599 lower or less frequent dose should be used in patients with cirrhosis. 600 Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or 601 norfluoxetine in plasma (see Renal disease under CLINICAL PHARMACOLOGY). Use of a 602 lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE 603 AND ADMINISTRATION). 604 In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred 605 during therapy with Prozac, and hyperglycemia has developed following discontinuation of the 606 drug. As is true with many other types of medication when taken concurrently by patients with 607 diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with 608 Prozac is instituted or discontinued. 609 Interference with Cognitive and Motor Performance — Any psychoactive drug may impair 610 judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous 611 machinery, including automobiles, until they are reasonably certain that the drug treatment does 612 not affect them adversely. 613 Discontinuation of Treatment with Prozac — During marketing of Prozac and other SSRIs 614 and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous 615 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 reports of adverse events occurring upon discontinuation of these drugs, particularly when 616 abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory 617 disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, 618 lethargy, emotional lability, insomnia, and hypomania. While these events are generally 619 self-limiting, there have been reports of serious discontinuation symptoms. Patients should be 620 monitored for these symptoms when discontinuing treatment with Prozac. A gradual reduction in 621 the dose rather than abrupt cessation is recommended whenever possible. If intolerable 622 symptoms occur following a decrease in the dose or upon discontinuation of treatment, then 623 resuming the previously prescribed dose may be considered. Subsequently, the physician may 624 continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine 625 concentration decrease gradually at the conclusion of therapy, which may minimize the risk of 626 discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION). 627 Information for Patients 628 Prescribers or other health professionals should inform patients, their families, and their 629 caregivers about the benefits and risks associated with treatment with Prozac and should counsel 630 them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, 631 Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available 632 for Prozac. The prescriber or health professional should instruct patients, their families, and their 633 caregivers to read the Medication Guide and should assist them in understanding its contents. 634 Patients should be given the opportunity to discuss the contents of the Medication Guide and to 635 obtain answers to any questions they may have. The complete text of the Medication Guide is 636 reprinted at the end of this document. 637 Patients should be advised of the following issues and asked to alert their prescriber if these 638 occur while taking Prozac. 639 Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should 640 be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, 641 irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), 642 hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal 643 ideation, especially early during antidepressant treatment and when the dose is adjusted up or 644 down. Families and caregivers of patients should be advised to look for the emergence of such 645 symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be 646 reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in 647 onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be 648 associated with an increased risk for suicidal thinking and behavior and indicate a need for very 649 close monitoring and possibly changes in the medication. 650 Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome 651 with the concomitant use of Prozac and triptans, tramadol or other serotonergic agents. 652 Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to 653 avoid driving a car or operating hazardous machinery until they are reasonably certain that their 654 performance is not affected. 655 Patients should be advised to inform their physician if they are taking or plan to take any 656 prescription or over-the-counter drugs, or alcohol. 657 Abnormal Bleeding— Patients should be cautioned about the concomitant use of fluoxetine 658 and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of 659 psychotropic drugs that interfere with serotonin reuptake and these agents have been associated 660 with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). 661 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Patients should be advised to notify their physician if they become pregnant or intend to 662 become pregnant during therapy. 663 Patients should be advised to notify their physician if they are breast-feeding an infant. 664 Patients should be advised to notify their physician if they develop a rash or hives. 665 Laboratory Tests 666 There are no specific laboratory tests recommended. 667 Drug Interactions 668 As with all drugs, the potential for interaction by a variety of mechanisms (e.g., 669 pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see 670 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 671 Drugs metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make 672 individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. 673 Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including 674 certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), 675 and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with 676 caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system 677 and that have a relatively narrow therapeutic index (see list below) should be initiated at the low 678 end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the 679 previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If 680 fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by 681 CYP2D6, the need for decreased dose of the original medication should be considered. Drugs 682 with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, 683 vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death 684 potentially associated with elevated plasma levels of thioridazine, thioridazine should not be 685 administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been 686 discontinued (see CONTRAINDICATIONS and WARNINGS). 687 Drugs metabolized by CYP3A4 — In an in vivo interaction study involving coadministration 688 of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma 689 terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies 690 have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more 691 potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for 692 this enzyme, including astemizole, cisapride, and midazolam. These data indicate that 693 fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. 694 CNS active drugs — The risk of using Prozac in combination with other CNS active drugs has 695 not been systematically evaluated. Nonetheless, caution is advised if the concomitant 696 administration of Prozac and such drugs is required. In evaluating individual cases, consideration 697 should be given to using lower initial doses of the concomitantly administered drugs, using 698 conservative titration schedules, and monitoring of clinical status (see Accumulation and slow 699 elimination under CLINICAL PHARMACOLOGY). 700 Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed 701 elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following 702 initiation of concomitant fluoxetine treatment. 703 Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or 704 pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of 705 haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. 706 Clinical studies of pimozide with other antidepressants demonstrate an increase in drug 707 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not 708 been conducted, the potential for drug interactions or QTc prolongation warrants restricting the 709 concurrent use of pimozide and Prozac. Concomitant use of Prozac and pimozide is 710 contraindicated (see CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS 711 and WARNINGS. 712 Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in 713 some patients (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 714 Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma 715 concentrations and in further psychomotor performance decrement due to increased alprazolam 716 levels. 717 Lithium — There have been reports of both increased and decreased lithium levels when 718 lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased 719 serotonergic effects have been reported. Lithium levels should be monitored when these drugs 720 are administered concomitantly. 721 Tryptophan — Five patients receiving Prozac in combination with tryptophan experienced 722 adverse reactions, including agitation, restlessness, and gastrointestinal distress. 723 Monoamine oxidase inhibitors — See CONTRAINDICATIONS. 724 Other drugs effective in the treatment of major depressive disorder — In 2 studies, previously 725 stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold 726 when fluoxetine has been administered in combination. This influence may persist for 3 weeks or 727 longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and 728 plasma TCA concentrations may need to be monitored temporarily when fluoxetine is 729 coadministered or has been recently discontinued (see Accumulation and slow elimination under 730 CLINICAL PHARMACOLOGY, and Drugs metabolized by CYP2D6 under Drug Interactions). 731 Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including 732 Prozac, and the potential for serotonin syndrome, caution is advised when Prozac is 733 coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such 734 as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, 735 or St. John’s Wort (see Serotonin Syndrome under WARNINGS). The concomitant use of 736 Prozac with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). 737 Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an 738 SSRI and a triptan. If concomitant treatment of Prozac with a triptan is clinically warranted, 739 careful observation of the patient is advised, particularly during treatment initiation and dose 740 increases (see Serotonin Syndrome under WARNINGS). 741 Potential effects of coadministration of drugs tightly bound to plasma proteins — Because 742 fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking 743 another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in 744 plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may 745 result from displacement of protein-bound fluoxetine by other tightly-bound drugs (see 746 Accumulation and slow elimination under CLINICAL PHARMACOLOGY). 747 Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin, Warfarin) — Serotonin release by 748 platelets plays an important role in hemostasis. Epidemiological studies of the case-control and 749 cohort design that have demonstrated an association between use of psychotropic drugs that 750 interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also 751 shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered 752 anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs 753 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 are coadministered with warfarin. Patients receiving warfarin therapy should be carefully 754 monitored when fluoxetine is initiated or discontinued. 755 Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the 756 combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in 757 patients on fluoxetine receiving ECT treatment. 758 Carcinogenesis, Mutagenesis, Impairment of Fertility 759 There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. 760 Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times 761 the MRHD on a mg/m2 basis) was not observed. 762 Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at 763 doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, 764 the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no 765 evidence of carcinogenicity. 766 Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects 767 based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat 768 hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese 769 hamster bone marrow cells. 770 Impairment of fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 771 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that 772 fluoxetine had no adverse effects on fertility (see Pediatric Use). 773 Pregnancy 774 Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was 775 no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, 776 respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis) throughout 777 organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in 778 pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following 779 maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 780 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was 781 no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 782 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 783 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the 784 potential benefit justifies the potential risk to the fetus. 785 Nonteratogenic Effects — Neonates exposed to Prozac and other SSRIs or serotonin and 786 norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed 787 complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such 788 complications can arise immediately upon delivery. Reported clinical findings have included 789 respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, 790 vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and 791 constant crying. These features are consistent with either a direct toxic effect of SSRIs and 792 SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the 793 clinical picture is consistent with serotonin syndrome (see Monoamine oxidase inhibitors under 794 CONTRAINDICATIONS). 795 Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent 796 pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the 797 general population and is associated with substantial neonatal morbidity and mortality. In a 798 retrospective case-control study of 377 women whose infants were born with PPHN and 836 799 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 women whose infants were born healthy, the risk for developing PPHN was approximately 800 six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants 801 who had not been exposed to antidepressants during pregnancy. There is currently no 802 corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; 803 this is the first study that has investigated the potential risk. The study did not include enough 804 cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN 805 risk. 806 When treating a pregnant woman with Prozac during the third trimester, the physician should 807 carefully consider both the potential risks and benefits of treatment (see DOSAGE AND 808 ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 809 women with a history of major depression who were euthymic at the beginning of pregnancy, 810 women who discontinued antidepressant medication during pregnancy were more likely to 811 experience a relapse of major depression than women who continued antidepressant medication. 812 Labor and Delivery 813 The effect of Prozac on labor and delivery in humans is unknown. However, because 814 fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse 815 effects on the newborn, fluoxetine should be used during labor and delivery only if the potential 816 benefit justifies the potential risk to the fetus. 817 Nursing Mothers 818 Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In 819 one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The 820 concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were 821 reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep 822 disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of 823 fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. 824 Pediatric Use 825 The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 826 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 (see 827 CLINICAL TRIALS). 828 The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week 829 placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see CLINICAL 830 TRIALS). 831 The safety and effectiveness in pediatric patients <8 years of age in major depressive disorder 832 and <7 years of age in OCD have not been established. 833 Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major 834 depressive disorder or OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY). 835 The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 836 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies 837 with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive 838 disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar 839 to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS). 840 Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out 841 of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. 842 Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the 843 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of 844 mania/hypomania is recommended. 845 As with other SSRIs, decreased weight gain has been observed in association with the use of 846 fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, 847 pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) 848 and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine 849 treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine 850 treatment for pediatric patients has not been systematically assessed for chronic treatment longer 851 than several months in duration. In particular, there are no studies that directly evaluate the 852 longer-term effects of fluoxetine on the growth, development, and maturation of children and 853 adolescent patients. Therefore, height and weight should be monitored periodically in pediatric 854 patients receiving fluoxetine. 855 (See WARNINGS, Clinical Worsening and Suicide Risk.) 856 Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive 857 toxicity, and impaired bone development, has been observed following exposure of juvenile 858 animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. 859 In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from 860 weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development 861 was delayed at all doses, and growth (body weight gain, femur length) was decreased during the 862 dosing period in animals receiving the highest dose. At the end of the treatment period, serum 863 levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high 864 doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle 865 degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and 866 hypospermia) was observed at the high dose. When animals were evaluated after a recovery 867 period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased 868 reactivity at all doses and learning deficit at the high dose) and reproductive functional 869 impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in 870 addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were 871 found in the high dose group, indicating that the reproductive organ effects seen at the end of 872 treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not 873 assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the 874 juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma 875 exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in 876 this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in 877 pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat 878 exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 879 times, respectively, pediatric exposure at the MRD. 880 A specific effect of fluoxetine on bone development has been reported in mice treated with 881 fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, 882 intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in 883 decreased bone mineral content and density. These doses did not affect overall growth (body 884 weight gain or femoral length). The doses administered to juvenile mice in this study are 885 approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) 886 basis. 887 In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early 888 postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors 889 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in 890 adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric 891 MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of 892 these findings to the approved pediatric use in humans is uncertain. 893 Prozac is approved for use in pediatric patients with MDD and OCD (see BOX WARNING 894 and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Prozac 895 in a child or adolescent must balance the potential risks with the clinical need. 896 Geriatric Use 897 US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years 898 of age. The efficacy in geriatric patients has been established (see CLINICAL TRIALS). For 899 pharmacokinetic information in geriatric patients, see Age under CLINICAL 900 PHARMACOLOGY. No overall differences in safety or effectiveness were observed between 901 these subjects and younger subjects, and other reported clinical experience has not identified 902 differences in responses between the elderly and younger patients, but greater sensitivity of some 903 older individuals cannot be ruled out. SSRIs and SNRIs, including Prozac, have been associated 904 with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk 905 for this adverse event (see PRECAUTIONS, Hyponatremia). 906 ADVERSE REACTIONS 907 Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in 908 US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered 909 Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using 910 descriptive terminology of their own choosing. Consequently, it is not possible to provide a 911 meaningful estimate of the proportion of individuals experiencing adverse events without first 912 grouping similar types of events into a limited (i.e., reduced) number of standardized event 913 categories. 914 In the tables and tabulations that follow, COSTART Dictionary terminology has been used to 915 classify reported adverse events. The stated frequencies represent the proportion of individuals 916 who experienced, at least once, a treatment-emergent adverse event of the type listed. An event 917 was considered treatment-emergent if it occurred for the first time or worsened while receiving 918 therapy following baseline evaluation. It is important to emphasize that events reported during 919 therapy were not necessarily caused by it. 920 The prescriber should be aware that the figures in the tables and tabulations cannot be used to 921 predict the incidence of side effects in the course of usual medical practice where patient 922 characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, 923 the cited frequencies cannot be compared with figures obtained from other clinical investigations 924 involving different treatments, uses, and investigators. The cited figures, however, do provide the 925 prescribing physician with some basis for estimating the relative contribution of drug and 926 nondrug factors to the side effect incidence rate in the population studied. 927 Incidence in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled 928 clinical trials (excluding data from extensions of trials) — Table 2 enumerates the most common 929 treatment-emergent adverse events associated with the use of Prozac (incidence of at least 5% for 930 Prozac and at least twice that for placebo within at least 1 of the indications) for the treatment of 931 major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder 932 in US plus non-US controlled trials. Table 3 enumerates treatment-emergent adverse events that 933 occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who 934 participated in US major depressive disorder, OCD, and bulimia controlled clinical trials and US 935 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 plus non-US panic disorder controlled clinical trials. Table 3 provides combined data for the pool 936 of studies that are provided separately by indication in Table 2. 937 938 Table 2: Most Common Treatment-Emergent Adverse Events: Incidence in Major 939 Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical 940 Trials1 941 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Event Prozac (N=1728) Placebo (N=975) Prozac (N=266) Placebo (N=89) Prozac (N=450) Placebo (N=267) Prozac (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence2 2 -- -- -- 7 -- 1 -- Abnormal ejaculation2 -- -- 7 -- 7 -- 2 1 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US 942 data for panic disorder clinical trials. 943 2 Denominator used was for males only (N=690 Prozac major depressive disorder; N=410 placebo major 944 depressive disorder; N=116 Prozac OCD; N=43 placebo OCD; N=14 Prozac bulimia; N=1 placebo bulimia; 945 N=162 Prozac panic; N=121 placebo panic). 946 -- Incidence less than 1%. 947 948 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Table 3: Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, 949 OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 950 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Event2 Prozac (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US 951 data for panic disorder clinical trials. 952 2 Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an 953 incidence on placebo ≥ Prozac (major depressive disorder, OCD, bulimia, and panic disorder combined): 954 abdominal pain, abnormal dreams, accidental injury, back pain, cough increased, major depressive disorder 955 (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis. 956 -- Incidence less than 1%. 957 958 Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic 959 disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 4 960 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least 961 twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event 962 associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder 963 clinical trials, plus non-US panic disorder clinical trials. 964 965 Table 4: Most Common Adverse Events Associated with Discontinuation in Major 966 Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical 967 Trials1 968 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- 1 Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic 969 disorder clinical trials. 970 971 Other adverse events in pediatric patients (children and adolescents) — Treatment-emergent 972 adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 973 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult 974 studies, as shown in Tables 2 and 3. However, the following adverse events (excluding those 975 which appear in the body or footnotes of Tables 2 and 3 and those for which the COSTART 976 terms were uninformative or misleading) were reported at an incidence of at least 2% for 977 fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, 978 epistaxis, urinary frequency, and menorrhagia. 979 The most common adverse event (incidence at least 1% for fluoxetine and greater than 980 placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 981 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for 982 fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event 983 associated with discontinuation was collected. 984 Events observed in Prozac Weekly clinical trials — Treatment-emergent adverse events in 985 clinical trials with Prozac Weekly were similar to the adverse events reported by patients in 986 clinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking Prozac 987 Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking 988 Prozac 20 mg daily (10% versus 5%, respectively). 989 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual 990 performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they 991 may also be a consequence of pharmacologic treatment. In particular, some evidence suggests 992 that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and 993 severity of untoward experiences involving sexual desire, performance, and satisfaction are 994 difficult to obtain, however, in part because patients and physicians may be reluctant to discuss 995 them. Accordingly, estimates of the incidence of untoward sexual experience and performance, 996 cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in 997 US major depressive disorder, OCD, and bulimia placebo-controlled clinical trials, decreased 998 libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% 999 fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of 1000 orgasmic dysfunction, including anorgasmia. 1001 There are no adequate and well-controlled studies examining sexual dysfunction with 1002 fluoxetine treatment. 1003 Priapism has been reported with all SSRIs. 1004 While it is difficult to know the precise risk of sexual dysfunction associated with the use of 1005 SSRIs, physicians should routinely inquire about such possible side effects. 1006 Other Events Observed in Clinical Trials 1007 Following is a list of all treatment-emergent adverse events reported at anytime by individuals 1008 taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed 1009 in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the 1010 COSTART terms were uninformative or misleading; (3) those events for which a causal 1011 relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient 1012 treated with Prozac and which did not have a substantial probability of being acutely 1013 life-threatening. 1014 Events are classified within body system categories using the following definitions: frequent 1015 adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; 1016 infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those 1017 occurring in less than 1/1000 patients. 1018 Body as a Whole — Frequent: chest pain, chills; Infrequent: chills and fever, face edema, 1019 intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, 1020 hypothermia, intentional injury, neuroleptic malignant syndrome1, photosensitivity reaction. 1021 Cardiovascular System — Frequent: hemorrhage, hypertension, palpitation; Infrequent: 1022 angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, 1023 postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, 1024 bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart 1025 arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, 1026 thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. 1027 Digestive System — Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous 1028 stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, 1029 glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, 1030 melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: 1031 biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal 1032 incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, 1033 intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary 1034 gland enlargement, stomach ulcer hemorrhage, tongue edema. 1035 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. 1036 Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, 1037 hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, 1038 thrombocythemia, thrombocytopenia. 1039 Metabolic and Nutritional — Frequent: weight gain; Infrequent: dehydration, generalized 1040 edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol 1041 intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, 1042 hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. 1043 Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, 1044 tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, 1045 osteomyelitis, osteoporosis, rheumatoid arthritis. 1046 Nervous System — Frequent: agitation, amnesia, confusion, emotional lability, sleep 1047 disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal 1048 syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, 1049 hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, 1050 neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder2, psychosis, vertigo; 1051 Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, 1052 delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, 1053 paralysis, reflexes decreased, reflexes increased, stupor. 1054 Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, 1055 atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, 1056 lung edema, pneumothorax, stridor. 1057 Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, 1058 maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, 1059 herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. 1060 Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry 1061 eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye 1062 hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field 1063 defect. 1064 Urogenital System — Frequent: urinary frequency; Infrequent: abortion3, albuminuria, 1065 amenorrhea3, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation3, 1066 fibrocystic breast3, hematuria, leukorrhea3, menorrhagia3, metrorrhagia3, nocturia, polyuria, 1067 urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage3; Rare: breast 1068 engorgement, glycosuria, hypomenorrhea3, kidney pain, oliguria, priapism3, uterine 1069 hemorrhage3, uterine fibroids enlarged3. 1070 1 Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. 1071 2 Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. 1072 3 Adjusted for gender. 1073 1074 Postintroduction Reports 1075 Voluntary reports of adverse events temporally associated with Prozac that have been received 1076 since market introduction and that may have no causal relationship with the drug include the 1077 following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic 1078 jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory 1079 syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 1080 weeks of fluoxetine therapy and which completely resolved over the next few months following 1081 drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, 1082 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, 1083 hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, 1084 misuse/abuse, movement disorders developing in patients with risk factors including drugs 1085 associated with such events and worsening of preexisting movement disorders, neuroleptic 1086 malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary 1087 embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and 1088 symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), 1089 Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, 1090 thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia 1091 (including torsades de pointes-type arrhythmias), and violent behaviors. 1092 DRUG ABUSE AND DEPENDENCE 1093 Controlled substance class — Prozac is not a controlled substance. 1094 Physical and psychological dependence — Prozac has not been systematically studied, in 1095 animals or humans, for its potential for abuse, tolerance, or physical dependence. While the 1096 premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal 1097 syndrome or any drug seeking behavior, these observations were not systematic and it is not 1098 possible to predict on the basis of this limited experience the extent to which a CNS active drug 1099 will be misused, diverted, and/or abused once marketed. Consequently, physicians should 1100 carefully evaluate patients for history of drug abuse and follow such patients closely, observing 1101 them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of 1102 dose, drug-seeking behavior). 1103 OVERDOSAGE 1104 Human Experience 1105 Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients 1106 (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with 1107 other drugs, reported from this population, there were 195 deaths. 1108 Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a 1109 fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, 1110 including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, 1111 pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, 1112 and hypomania. The remaining 206 patients had an unknown outcome. The most common signs 1113 and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, 1114 tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult 1115 patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. 1116 However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been 1117 associated with lethal outcome, but causality has not been established. 1118 Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose 1119 involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients 1120 completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown 1121 outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s 1122 syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 1123 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and 1124 promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in 1125 children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which 1126 was nonlethal. 1127 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 Other important adverse events reported with fluoxetine overdose (single or multiple drugs) 1128 include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular 1129 tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic 1130 malignant syndrome-like events, pyrexia, stupor, and syncope. 1131 Animal Experience 1132 Studies in animals do not provide precise or necessarily valid information about the treatment 1133 of human overdose. However, animal experiments can provide useful insights into possible 1134 treatment strategies. 1135 The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. 1136 Acute high oral doses produced hyperirritability and convulsions in several animal species. 1137 Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. 1138 Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary 1139 dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure 1140 occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, 1141 chronically. 1142 In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation 1143 of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. 1144 Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the 1145 ECG should ordinarily be monitored in cases of human overdose (see Management of 1146 Overdose). 1147 Management of Overdose 1148 Treatment should consist of those general measures employed in the management of 1149 overdosage with any drug effective in the treatment of major depressive disorder. 1150 Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital 1151 signs. General supportive and symptomatic measures are also recommended. Induction of emesis 1152 is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway 1153 protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic 1154 patients. 1155 Activated charcoal should be administered. Due to the large volume of distribution of this 1156 drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of 1157 benefit. No specific antidotes for fluoxetine are known. 1158 A specific caution involves patients who are taking or have recently taken fluoxetine and might 1159 ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or 1160 an active metabolite may increase the possibility of clinically significant sequelae and extend the 1161 time needed for close medical observation (see Other drugs effective in the treatment of major 1162 depressive disorder under PRECAUTIONS). 1163 Based on experience in animals, which may not be relevant to humans, fluoxetine-induced 1164 seizures that fail to remit spontaneously may respond to diazepam. 1165 In managing overdosage, consider the possibility of multiple drug involvement. The physician 1166 should consider contacting a poison control center for additional information on the treatment of 1167 any overdose. Telephone numbers for certified poison control centers are listed in the 1168 Physicians’ Desk Reference (PDR). 1169 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 DOSAGE AND ADMINISTRATION 1170 Major Depressive Disorder 1171 Initial Treatment 1172 Adult — In controlled trials used to support the efficacy of fluoxetine, patients were 1173 administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, 1174 and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response 1175 in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in 1176 the morning, is recommended as the initial dose. 1177 A dose increase may be considered after several weeks if insufficient clinical improvement is 1178 observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID 1179 schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. 1180 Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials 1181 of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients 1182 were administered fluoxetine doses of 10 to 20 mg/day (see CLINICAL TRIALS). Treatment 1183 should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should 1184 be increased to 20 mg/day. 1185 However, due to higher plasma levels in lower weight children, the starting and target dose in 1186 this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several 1187 weeks if insufficient clinical improvement is observed. 1188 All patients — As with other drugs effective in the treatment of major depressive disorder, the 1189 full effect may be delayed until 4 weeks of treatment or longer. 1190 As with many other medications, a lower or less frequent dosage should be used in patients 1191 with hepatic impairment. A lower or less frequent dosage should also be considered for the 1192 elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or 1193 on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely 1194 necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use 1195 in Patients with Concomitant Illness under PRECAUTIONS). 1196 Maintenance/Continuation/Extended Treatment 1197 It is generally agreed that acute episodes of major depressive disorder require several months 1198 or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is 1199 identical to the dose needed to maintain and/or sustain euthymia is unknown. 1200 Daily Dosing 1201 Systematic evaluation of Prozac in adult patients has shown that its efficacy in major 1202 depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of 1203 open-label acute treatment (50 weeks total) at a dose of 20 mg/day (see CLINICAL TRIALS). 1204 Weekly Dosing 1205 Systematic evaluation of Prozac Weekly in adult patients has shown that its efficacy in major 1206 depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosing 1207 following 13 weeks of open-label treatment with Prozac 20 mg once daily. However, therapeutic 1208 equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mg given daily for 1209 delaying time to relapse has not been established (see CLINICAL TRIALS). 1210 Weekly dosing with Prozac Weekly capsules is recommended to be initiated 7 days after the 1211 last daily dose of Prozac 20 mg (see Weekly dosing under CLINICAL PHARMACOLOGY). 1212 If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily 1213 dosing regimen (see CLINICAL TRIALS). 1214 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Switching Patients to a Tricyclic Antidepressant (TCA) 1215 Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be 1216 monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see 1217 Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS, Drug 1218 Interactions). 1219 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) 1220 At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy 1221 with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping 1222 Prozac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS). 1223 Obsessive Compulsive Disorder 1224 Initial Treatment 1225 Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the 1226 treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine 1227 or placebo (see CLINICAL TRIALS). In 1 of these studies, no dose-response relationship for 1228 effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the 1229 morning, is recommended as the initial dose. Since there was a suggestion of a possible 1230 dose-response relationship for effectiveness in the second study, a dose increase may be 1231 considered after several weeks if insufficient clinical improvement is observed. The full 1232 therapeutic effect may be delayed until 5 weeks of treatment or longer. 1233 Doses above 20 mg/day may be administered on a once-a-day (i.e., morning) or BID schedule 1234 (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of 1235 up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose 1236 should not exceed 80 mg/day. 1237 Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting 1238 its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the 1239 range of 10 to 60 mg/day (see CLINICAL TRIALS). 1240 In adolescents and higher weight children, treatment should be initiated with a dose of 1241 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases 1242 may be considered after several more weeks if insufficient clinical improvement is observed. A 1243 dose range of 20 to 60 mg/day is recommended. 1244 In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional 1245 dose increases may be considered after several more weeks if insufficient clinical improvement 1246 is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses 1247 greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. 1248 All patients — As with the use of Prozac in the treatment of major depressive disorder, a lower 1249 or less frequent dosage should be used in patients with hepatic impairment. A lower or less 1250 frequent dosage should also be considered for the elderly (see Geriatric Use under 1251 PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant 1252 medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver 1253 disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with 1254 Concomitant Illness under PRECAUTIONS). 1255 Maintenance/Continuation Treatment 1256 While there are no systematic studies that answer the question of how long to continue Prozac, 1257 OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. 1258 Although the efficacy of Prozac after 13 weeks has not been documented in controlled trials, 1259 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 adult patients have been continued in therapy under double-blind conditions for up to an 1260 additional 6 months without loss of benefit. However, dosage adjustments should be made to 1261 maintain the patient on the lowest effective dosage, and patients should be periodically 1262 reassessed to determine the need for treatment. 1263 Bulimia Nervosa 1264 Initial Treatment 1265 In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of 1266 bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or 1267 placebo (see CLINICAL TRIALS). Only the 60-mg dose was statistically significantly superior 1268 to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the 1269 recommended dose is 60 mg/day, administered in the morning. For some patients it may be 1270 advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day 1271 have not been systematically studied in patients with bulimia. 1272 As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or 1273 less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent 1274 dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and 1275 for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments 1276 for renal impairment are not routinely necessary (see Liver disease and Renal disease under 1277 CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under 1278 PRECAUTIONS). 1279 Maintenance/Continuation Treatment 1280 Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in 1281 patients with bulimia who have responded while taking Prozac 60 mg/day during an 8-week 1282 acute treatment phase has demonstrated a benefit of such maintenance treatment (see CLINICAL 1283 TRIALS). Nevertheless, patients should be periodically reassessed to determine the need for 1284 maintenance treatment. 1285 Panic Disorder 1286 Initial Treatment 1287 In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of 1288 panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see 1289 CLINICAL TRIALS). Treatment should be initiated with a dose of 10 mg/day. After 1 week, the 1290 dose should be increased to 20 mg/day. The most frequently administered dose in the 2 1291 flexible-dose clinical trials was 20 mg/day. 1292 A dose increase may be considered after several weeks if no clinical improvement is observed. 1293 Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic 1294 disorder. 1295 As with the use of Prozac in other indications, a lower or less frequent dosage should be used 1296 in patients with hepatic impairment. A lower or less frequent dosage should also be considered 1297 for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent 1298 disease or on multiple concomitant medications. Dosage adjustments for renal impairment are 1299 not routinely necessary (see Liver disease and Renal disease under CLINICAL 1300 PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). 1301 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 Maintenance/Continuation Treatment 1302 While there are no systematic studies that answer the question of how long to continue Prozac, 1303 panic disorder is a chronic condition and it is reasonable to consider continuation for a 1304 responding patient. Nevertheless, patients should be periodically reassessed to determine the 1305 need for continued treatment. 1306 Special Populations 1307 Treatment of Pregnant Women During the Third Trimester 1308 Neonates exposed to Prozac and other SSRIs or SNRIs, late in the third trimester have 1309 developed complications requiring prolonged hospitalization, respiratory support, and tube 1310 feeding (see PRECAUTIONS). When treating pregnant women with Prozac during the third 1311 trimester, the physician should carefully consider the potential risks and benefits of treatment. 1312 The physician may consider tapering Prozac in the third trimester. 1313 Discontinuation of Treatment with Prozac 1314 Symptoms associated with discontinuation of Prozac and other SSRIs and SNRIs, have been 1315 reported (see PRECAUTIONS). Patients should be monitored for these symptoms when 1316 discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is 1317 recommended whenever possible. If intolerable symptoms occur following a decrease in the dose 1318 or upon discontinuation of treatment, then resuming the previously prescribed dose may be 1319 considered. Subsequently, the physician may continue decreasing the dose but at a more gradual 1320 rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of 1321 therapy which may minimize the risk of discontinuation symptoms with this drug. 1322 HOW SUPPLIED 1323 The following products are manufactured by Eli Lilly and Company for Dista Products 1324 Company. 1325 1326 Prozac® Pulvules®, USP, are available in: The 10-mg1, Pulvule is opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body: NDC 0777-3104-02 (PU31042) - Bottles of 100 The 20-mg1 Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body: NDC 0777-3105-30 (PU31052) - Bottles of 30 NDC 0777-3105-02 (PU31052) - Bottles of 100 NDC 0777-3105-07 (PU31052) - Bottles of 2000 The 40-mg1 Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU31072) - Bottles of 30 The following is manufactured by OSG Norwich Pharmaceuticals, Inc., North Norwich, NY, 13814, for Dista Products Company: Liquid, Oral Solution is available in: 20 mg1 per 5 mL with mint flavor: NDC 0777-5120-58 (MS-51203) - Bottles of 120 mL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 The following product is manufactured and distributed by Eli Lilly and Company: Prozac® Weekly™ Capsules are available in: The 90-mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) - Blister package of 4 ______________________ 1327 1 Fluoxetine base equivalent. 1328 2 Protect from light. 1329 3 Dispense in a tight, light-resistant container. 1330 1331 Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). 1332 ANIMAL TOXICOLOGY 1333 Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine 1334 chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid 1335 accumulation in animals has been observed with many cationic amphiphilic drugs, including 1336 fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. 1337 Literature revised January 16, 2008 1338 Eli Lilly and Company 1339 Indianapolis, IN 46285, USA 1340 1341 www.lilly.com 1342 PV 5326 DPP PRINTED IN USA 1343 Medication Guide 1344 Antidepressant Medicines, Depression and other Serious Mental 1345 Illnesses, and Suicidal Thoughts or Actions 1346 Read the Medication Guide that comes with your or your family member’s antidepressant 1347 medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with 1348 antidepressant medicines. Talk to your, or your family member’s, healthcare provider 1349 about: 1350 • all risks and benefits of treatment with antidepressant medicines 1351 • all treatment choices for depression or other serious mental illness 1352 What is the most important information I should know about antidepressant 1353 medicines, depression and other serious mental illnesses, and suicidal thoughts 1354 or actions? 1355 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, 1356 teenagers, and young adults within the first few months of treatment. 1357 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 2. Depression and other serious mental illnesses are the most important causes of 1358 suicidal thoughts and actions. Some people may have a particularly high risk of 1359 having suicidal thoughts or actions. These include people who have (or have a family 1360 history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or 1361 actions. 1362 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a 1363 family member? 1364 • Pay close attention to any changes, especially sudden changes, in mood, behaviors, 1365 thoughts, or feelings. This is very important when an antidepressant medicine is 1366 started or when the dose is changed. 1367 • Call the healthcare provider right away to report new or sudden changes in mood, 1368 behavior, thoughts, or feelings. 1369 • Keep all follow-up visits with the healthcare provider as scheduled. Call the 1370 healthcare provider between visits as needed, especially if you have concerns about 1371 symptoms. 1372 Call a healthcare provider right away if you or your family member has any of the 1373 following symptoms, especially if they are new, worse, or worry you: 1374 • thoughts about suicide or dying 1375 • attempts to commit suicide 1376 • new or worse depression 1377 • new or worse anxiety 1378 • feeling very agitated or restless 1379 • panic attacks 1380 • trouble sleeping (insomnia) 1381 • new or worse irritability 1382 • acting aggressive, being angry, or violent 1383 • acting on dangerous impulses 1384 • an extreme increase in activity and talking (mania) 1385 • other unusual changes in behavior or mood 1386 What else do I need to know about antidepressant medicines? 1387 • Never stop an antidepressant medicine without first talking to a healthcare provider. 1388 Stopping an antidepressant medicine suddenly can cause other symptoms. 1389 • Antidepressants are medicines used to treat depression and other illnesses. It is 1390 important to discuss all the risks of treating depression and also the risks of not treating it. 1391 Patients and their families or other caregivers should discuss all treatment choices with the 1392 healthcare provider, not just the use of antidepressants. 1393 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 • Antidepressant medicines have other side effects. Talk to the healthcare provider about 1394 the side effects of the medicine prescribed for you or your family member. 1395 • Antidepressant medicines can interact with other medicines. Know all of the medicines 1396 that you or your family member takes. Keep a list of all medicines to show the healthcare 1397 provider. Do not start new medicines without first checking with your healthcare provider. 1398 • Not all antidepressant medicines prescribed for children are FDA approved for use in 1399 children. Talk to your child’s healthcare provider for more information. 1400 This Medication Guide has been approved by the US Food and Drug Administration for 1401 all antidepressants. 1402 Patient Information revised June 21, 2007 1403 PV 5083 AMP 1404 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:44.486115	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018936s084,020101s039,021235s011lbl.pdf', 'application_number': 20101, 'submission_type': 'SUPPL ', 'submission_number': 39}
12,210	MIVACRON® Injection (mivacurium chloride) This drug should be administered only by adequately trained individuals familiar with its actions, characteristics, and hazards. DESCRIPTION MIVACRON (mivacurium chloride) is a short-acting, nondepolarizing skeletal muscle relaxant for intravenous (IV) administration. Mivacurium chloride is [R-[R,R-(E)]]-2,2'-[(1,8-dioxo-4 octene-1,8-diyl)bis(oxy-3,1-propanediyl)]bis[1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1 [(3,4,5-trimethoxyphenyl)methyl]isoquinolinium] dichloride. The molecular formula is C58H80Cl2N2O14 and the molecular weight is 1100.18. The structural formula is: The partition coefficient of the compound is 0.015 in a 1-octanol/distilled water system at 25°C. Mivacurium chloride is a mixture of three stereoisomers: (1R,1'R , 2S, 2'S ), the trans-trans diester; (1R,1'R , 2R, 2'S ), the cis-trans diester; and (1R,1'R , 2R, 2'R ), the cis-cis diester. The trans-trans and cis-trans stereoisomers comprise 92% to 96% of mivacurium chloride and their neuromuscular blocking potencies are not significantly different from each other or from mivacurium chloride. The cis-cis diester has been estimated from studies in cats to have one- tenth the neuromuscular blocking potency of the other two stereoisomers. MIVACRON Injection is a sterile, non-pyrogenic solution (pH 3.5 to 5) containing mivacurium chloride equivalent to 2 mg/mL mivacurium in Water for Injection. Hydrochloric acid may have been added to adjust pH. CLINICAL PHARMACOLOGY MIVACRON (a mixture of three stereoisomers) binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in a block of neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine. dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacodynamics The time to maximum neuromuscular block is similar for recommended doses of MIVACRON and intermediate-acting agents (e.g., atracurium), but longer than for the ultra-short-acting agent, succinylcholine. The clinically effective duration of action of MIVACRON (a mixture of three stereoisomers) is one-third to one-half that of intermediate-acting agents and 2 to 2.5 times that of succinylcholine. The average ED95 (dose required to produce 95% suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) of MIVACRON is 0.07 mg/kg (range: 0.05 mg/kg to 0.09 mg/kg) in adults receiving opioid/nitrous oxide/oxygen anesthesia. The pharmacodynamics of doses of MIVACRON greater than or equal to ED95 administered over 5 to 15 seconds during opioid/nitrous oxide/oxygen anesthesia are summarized in Table 1. The mean time for spontaneous recovery of the twitch response from 25% to 75% of control amplitude is about 6 minutes (range: 3 to 9 minutes, n = 32) following an initial dose of 0.15 mg/kg MIVACRON and 7 to 8 minutes (range: 4 to 24 minutes, n = 85) following initial doses of 0.2 or 0.25 mg/kg MIVACRON. Volatile anesthetics may decrease the dosing requirement for MIVACRON and prolong the duration of action; the magnitude of these effects may be increased as the concentration of the volatile agent is increased. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 MAC [Minimum Alveolar Concentration]) may decrease the effective dose of MIVACRON by as much as 25%, and may prolong the clinically effective duration of action and decrease the average infusion requirement by as much as 35% to 40%. At equivalent MAC values, halothane has little or no effect on the ED50 of MIVACRON, but may prolong the duration of action and decrease the average infusion requirement by as much as 20% (see CLINICAL PHARMACOLOGY - Individualization of Dosages subsection and PRECAUTIONS - Drug Interactions). Table 1. Pharmacodynamic Dose Response During Opioid/Nitrous Oxide/Oxygen Anesthesia Time to Spontaneous Recovery† Initial Dose of MIVACRON* (mg/kg) Time to Maximum Block† (min) 5% Recovery (min) 25% Recovery‡ (min) 95% Recovery§ (min) T4/T 1 Ratio ≥ 75%§ (min) Adults 0.07 to 0.1 [n = 47] 4.9 (2-7.6) 11 (7-19) 13 (8-24) 21 (10-36) 21 (10-36) 0.15 [n = 50] 3.3 (1.5-8.8) 13 (6-31) 16 (9-38) 26 (16-41) 26 (15-45) 0.2\|\| [n = 50] 2.5 (1.2-6) 16 (10-29) 20 (10-36) 31 (15-51) 34 (19-56) 0.25\|\| [n = 48] 2.3 (1-4.8) 19 (11-29) 23 (14-38) 34 (22-64) 43 (26-75) Children 2 to 12 Years 0.11 to 0.12 [n = 17] 2.8 (1.2-4.6) 5 (3-9) 7 (4-10) – – 0.2 [n = 18] 1.9 (1.3-3.3) 7 (3-12) 10 (6-15) 19 (14-26) 16 (12-23) 0.25 [n = 9] 1.6 (1-2.2) 7 (4-9) 9 (5-12) – – * Doses administered over 5 to 15 seconds. dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda † Values shown are medians of means from individual studies (range of individual patient values). ‡ Clinically effective duration of neuromuscular block. § Data available for as few as 40% of adults in specific dose groups and for 22% of children in the 0.2 mg/kg dose group due to administration of reversal agents or additional doses of MIVACRON prior to 95% recovery or T4/T1 ratio recovery to greater than or equal to 75%. \|\| Rapid administration not recommended due to possibility of decreased blood pressure. Administer 0.2 mg/kg over 30 seconds; administer 0.25 mg/kg as divided dose (0.15 mg/kg followed 30 seconds later by 0.1 mg/kg). (See DOSAGE AND ADMINISTRATION.) Administration of MIVACRON over 30 to 60 seconds does not alter the time to maximum neuromuscular block or the duration of action. The duration of action of MIVACRON may be prolonged in patients with reduced plasma cholinesterase (pseudocholinesterase) activity (see PRECAUTIONS - Reduced Plasma Cholinesterase Activity and CLINICAL PHARMACOLOGY - Individualization of Dosages subsection). Interpatient variability in duration of action occurs with MIVACRON as with other neuromuscular blocking agents. However, analysis of data from 224 patients in clinical studies receiving various doses of MIVACRON during opioid/nitrous oxide/oxygen anesthesia with a variety of premedicants and varying lengths of surgery indicated that approximately 90% of the patients had clinically effective durations of block within 8 minutes of the median duration predicted from the dose-response data shown in Table 1. Variations in plasma cholinesterase activity, including values within the normal range and values as low as 20% below the lower limit of the normal range, were not associated with clinically significant effects on duration. The variability in duration, however, was greater in patients with plasma cholinesterase activity at or slightly below the lower limit of the normal range. When administered during the induction of adequate anesthesia using thiopental or propofol, nitrous oxide/oxygen, and co-induction agents such as fentanyl and/or midazolam, doses of 0.15 mg/kg (2 x ED95) MIVACRON administered over 5 to 15 seconds or 0.2 mg/kg MIVACRON administered over 30 seconds produced generally good-to-excellent tracheal intubation conditions in 2.5 to 3 and 2 to 2.5 minutes, respectively. A dose of 0.25 mg/kg MIVACRON administered as a divided dose (0.15 mg/kg followed 30 seconds later by 0.1 mg/kg) produced generally good-to-excellent intubation conditions in 1.5 to 2 minutes after initiating the dosing regimen. Repeated administration of maintenance doses or continuous infusion of MIVACRON for up to 2.5 hours is not associated with development of tachyphylaxis or cumulative neuromuscular blocking effects in ASA Physical Status I-II patients. Based on pharmacokinetic studies in 82 adults receiving infusions of MIVACRON for longer than 2.5 hours, spontaneous recovery of neuromuscular function after infusion is independent of the duration of infusion and comparable to recovery reported for single doses (Table 1). MIVACRON was administered as an infusion for as long as 4 to 6 hours in 20 adult patients and 19 geriatric patients. In most patients, after a brief period of adjustment, the rate of MIVACRON required to maintain 89% to 99% T1 suppression remained relatively constant over time. There was a subset of patients in each group whose infusion rates did not stabilize quickly and decreased (by greater than or equal to 30%) over the period of infusion. The rate of spontaneous dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda recovery in these patients was comparable with that of patients having stable infusion rates and not dependent on the duration of infusion. These patients, however, tended to have higher infusion requirements (i.e., greater than 8 mcg/kg/min) during the first 30 minutes of infusion than patients with stable infusion rates, although their final infusion rates were similar to those with stable infusion rates. There were no clinically important differences in infusion rate requirements between geriatric and young patients (see Pharmacokinetics - Special Populations - Geriatric Patients). The neuromuscular block produced by MIVACRON is readily antagonized by anticholinesterase agents. As seen with other nondepolarizing neuromuscular blocking agents, the more profound the neuromuscular block at the time of reversal, the longer the time and the greater the dose of anticholinesterase agent required for recovery of neuromuscular function. In children (2 to 12 years), MIVACRON has a higher ED95 (0.1 mg/kg), faster onset, and shorter duration of action than in adults. The mean time for spontaneous recovery of the twitch response from 25% to 75% of control amplitude is about 5 minutes (n = 4) following an initial dose of 0.2 mg/kg MIVACRON. Recovery following reversal is faster in children than in adults (Table 1). Hemodynamics Administration of MIVACRON in doses up to and including 0.15 mg/kg (2 x ED95) over 5 to 15 seconds to ASA Physical Status I-II patients during opioid/nitrous oxide/oxygen anesthesia is associated with minimal changes in mean arterial blood pressure (MAP) or heart rate (HR) (Table 2). Table 2. Cardiovascular Dose Response During Opioid/Nitrous Oxide/Oxygen Anesthesia % of Patients With ≥ 30% Change MAP HR Initial Dose of MIVACRON* (mg/kg) Dec Inc Dec Inc Adults 0.07 to 0.1 [n = 49] 0% 2% 0% 0% 0.15 [n = 53] 4% 4% 4% 2% 0.2† [n = 53] 30% 0% 0% 8% 0.25† [n = 44] 39% 2% 0% 14% Children 2 to 12 years 0.11 to 0.12 [n = 17] 0% 6% 0% 0% 0.2 [n = 17] 0% 0% 0% 0% 0.25 [n = 8] 13% 0% 0% 0% * Doses administered over 5 to 15 seconds. † Rapid administration not recommended due to possibility of decreased blood pressure. Administer 0.2 mg/kg over 30 seconds; administer 0.25 mg/kg as divided dose (0.15 mg/kg followed 30 seconds later by 0.1 mg/kg). (See DOSAGE AND ADMINISTRATION.) Higher doses of greater than or equal to 0.2 mg/kg (greater than or equal to 3 x ED95) may be associated with transient decreases in MAP and increases in HR in some patients. These dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda decreases in MAP are usually maximal within 1 to 3 minutes following the dose, typically resolve without treatment in an additional 1 to 3 minutes, and are usually associated with increases in plasma histamine concentration. Decreases in MAP can be minimized by administering MIVACRON over 30 to 60 seconds (see CLINICAL PHARMACOLOGY Individualization of Dosages subsection and PRECAUTIONS - General). Analysis of 426 patients in clinical studies receiving initial doses of MIVACRON up to and including 0.3 mg/kg during opioid/nitrous oxide/oxygen anesthesia showed that high initial doses and a rapid rate of injection contributed to a greater probability of experiencing a decrease of greater than or equal to 30% in MAP after administration of MIVACRON. Obese patients also had a greater probability of experiencing a decrease of greater than or equal to 30% in MAP when dosed on the basis of actual body weight, thereby receiving a larger dose than if dosed on the basis of ideal body weight (see CLINICAL PHARMACOLOGY - Individualization of Dosages subsection and PRECAUTIONS - General). Children experience minimal changes in MAP or HR after administration of doses of MIVACRON up to and including 0.2 mg/kg over 5 to 15 seconds, but higher doses (greater than or equal to 0.25 mg/kg) may be associated with transient decreases in MAP (Table 2). Following a dose of 0.15 mg/kg MIVACRON administered over 60 seconds, adult patients with significant cardiovascular disease undergoing coronary artery bypass grafting or valve replacement procedures showed no clinically important changes in MAP or HR. Transient decreases in MAP were observed in some patients after doses of 0.2 to 0.25 mg/kg MIVACRON administered over 60 seconds. The number of patients in whom these decreases in MAP required treatment was small. Pharmacokinetics MIVACRON is a mixture of isomers which do not interconvert in vivo. The cis-trans and trans- trans isomers (92% to 96% of the mixture) are equipotent. The steady-state concentrations of the cis-trans and trans-trans isomers doubled after the infusion rate was increased from 5 to 10 mcg/kg/min, indicating that their pharmacokinetics is dose-proportional. Table 3. Stereoisomer Pharmacokinetic Parameters* of Mivacurium in ASA Physical Status I-II Adult Patients† [n = 18] During Opioid/Nitrous Oxide/Oxygen Anesthesia Parameter trans-trans isomer cis-trans isomer Elimination Half-life (t½ min) 2 (1-3.6) 1.8 (0.8-4.8) Volume of Distribution‡ (mL/kg) 147 (67-254) 276 (79-772) Plasma Clearance (mL/min/kg) 53 (26-98) 99 (44-199) * Values shown are mean (range). † Ages 31 to 48 years. ‡ Volume of distribution during the terminal elimination phase. The cis-cis isomer (6% of the mixture) has approximately one-tenth the neuromuscular blocking potency of the trans-trans and cis-trans isomers in cats. Neuromuscular blocking effects due to the cis-cis isomer cannot be ruled out in humans; however, modeling of clinical dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pharmacokinetic-pharmacodynamic data suggests that the cis-cis isomer produces minimal (less than 5%) neuromuscular block during a 2-hour infusion. In studies of ASA Physical Status I-II patients receiving infusions of MIVACRON lasting as long as 4 to 6 hours, the 5% to 25% and the 25% to 75% recovery indices were independent of the duration of infusion, suggesting that the cis-cis isomer does not affect the rate of post-infusion recovery. Distribution The volume of distribution of cis-trans and trans-trans isomers in healthy surgical patients is relatively small, reflecting limited tissue distribution (Table 3). The volume of distribution of cis- cis isomers is also small and averaged 335 mL/kg (range 192 to 523) in the 18 healthy surgical patients whose data are displayed in Table 3. The protein binding of mivacurium has not been determined due to its rapid hydrolysis by plasma cholinesterase. Metabolism Enzymatic hydrolysis by plasma cholinesterase is the primary mechanism for inactivation of mivacurium and yields a quaternary alcohol and a quaternary monoester metabolite. Tests in which these two metabolites were administered to cats and dogs suggest that each metabolite is unlikely to produce clinically significant neuromuscular, autonomic, or cardiovascular effects following administration of MIVACRON. The mean ± S.D. in vitro t½ values of the trans-trans and the cis-trans isomers were 1.3 ± 0.3 and 0.8 ± 0.2 minutes, respectively, in human plasma from healthy male (n = 5) and female (n = 5) volunteers. The mean in vivo t½ values for the more potent trans-trans and cis-trans isomers in healthy surgical patients (Table 3) were similar to those found in vitro , suggesting that hydrolysis by plasma cholinesterase is the predominant elimination pathway for these isomers. The mean ± S.D. in vitro t½ of the less potent cis-cis isomer was 276 ± 130 minutes, while the mean ± S.D. in vivo t½ for the cis-cis isomer in healthy surgical patients was 53 ± 20 minutes. These data suggest that in vivo , pathways other than hydrolysis by plasma cholinesterase contribute to the elimination of the cis-cis isomer. Elimination The clearance (CL) values of the two more potent isomers, cis-trans and trans-trans, are very high and are dependent on plasma cholinesterase activity (Table 3). The combination of high CL and low distribution volume results in t½ values of approximately 2 minutes for the two more potent isomers. The short t½ and high CL of the more potent isomers are consistent with the short duration of action of MIVACRON. The CL of the less potent cis-cis isomer is not dependent on plasma cholinesterase. The mean ± S.D. CL was 4.6 ± 1.1 mL/min/kg and t½ was 53 ± 20 minutes in the 18 healthy surgical patients whose data are displayed in Table 3. Renal and biliary excretion of unchanged mivacurium are minor elimination pathways; urine and bile are important elimination pathways for the two metabolites. Special Populations Geriatric Patients (greater than or equal to 60 years) dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Two pharmacokinetic/pharmacodynamic studies of MIVACRON have been conducted in geriatric patients. The first study compared the pharmacokinetics and pharmacodynamics of mivacurium in 19 geriatric patients with those in 20 adult patients receiving infusions for as long as 4 to 6 hours. The average infusion rate required to produce 89% to 99% T1 suppression was slightly (~ 14%) lower in geriatric patients. This difference is not regarded as clinically important, but is most likely secondary to differences in pharmacokinetics (i.e., a lower CL of the cis-trans and trans-trans isomers in geriatric patients) (Table 4). The rate of post-infusion spontaneous recovery was not dependent on duration of infusion and appeared to be comparable in these geriatric patients and adult patients. Two pharmacodynamic studies in which patients received infusions for a shorter duration (2 to 3 hours) have shown that the infusion rate requirements were lower (by 38%) in geriatric patients (64 to 86 years of age) than in younger patients (18 to 41 years of age). Table 4. Stereoisomer Pharmacokinetic Parameters* of Mivacurium in ASA Physical Status I-II Adult Patients [18-58 Years] and Geriatric Patients [60-81 Years] During Opioid/Nitrous Oxide/Oxygen Anesthesia Parameter Isomer Adult Patients (n = 12) Geriatric Patients (n = 8) Plasma Clearance (mL/min/kg) trans-trans isomer 54 (34 - 129) 32 (18 - 55) cis-trans isomer 91 (27 - 825) 47 (24 - 93) * Values shown are median (range). The second pharmacokinetic/pharmacodynamic study showed no clinically important differences in the pharmacokinetics of the individual isomers nor the ED95 determined for 36 young adult patients (18 to 40 years) and 35 geriatric patients (greater than or equal to 65 years) during opioid/nitrous oxide/oxygen anesthesia. Following infusions for up to 3.5 hours in these patients, the rate of spontaneous recovery was slightly (~ 2 to 4 minutes, on average) slower in the geriatric patients than in young adult patients. In a third study of the pharmacodynamics of 0.1 mg/kg MIVACRON administered to eight geriatric patients (68 to 77 years) and nine adult patients (18 to 49 years) during N2O/O2/isoflurane anesthesia, the time to onset was approximately 1.5 minutes slower in geriatric patients than in adult patients. In addition, the clinical duration was slightly (~ 3 minutes, on average) longer in geriatric patients than in adult patients; these differences are not considered clinically important. Although these studies showed conflicting findings, in general, the clearances of the more potent isomers are most likely lower in geriatric patients. This difference does not lead to clinically important differences in the ED95 of MIVACRON or the infusion rate of MIVACRON required to produce 95% T1 suppression in geriatric patients. However, the time to onset may be slower, the duration may be slightly longer, the rate of recovery may be slightly slower, therefore MIVACRON requirements may be lower in geriatric patients. Patients with Renal Disease dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda An early clinical trial showed that the clinically effective duration of action of 0.15 mg/kg MIVACRON was about 1.5 times longer in kidney transplant patients than in healthy patients, presumably due to reduced clearance of one or more isomers. A second study was conducted in seven patients with mild to moderate renal impairment, eight patients with severe renal dysfunction (not undergoing transplantation), and 11 patients with normal renal function. This study showed that the pharmacokinetics of the more potent (cis-trans and trans-trans) isomers were not statistically significantly affected by renal impairment or failure (Table 5). However, the CL of the cis-cis isomer was lower and the t½ values of the cis-cis isomer and metabolites were longer in patients with renal impairment or failure than in patients with normal renal function. The second study also showed that there were no differences in the average infusion rate required to produce 89% to 99% T1 suppression, nor were there any differences in the post- infusion recovery profile among these populations (Table 5). A third study in a similar population showed that patients with renal dysfunction had a longer duration and a slower rate of recovery than patients with normal renal function. This study did, however, confirm that there were no differences in the average infusion rate required to produce 89% to 99% T1 suppression in these patient populations. Therefore, although there were minor differences in the pharmacokinetics of the cis-cis isomer and metabolites, there were no clinically significant differences in the infusion rate requirements of MIVACRON in patients with mild, moderate, or severe renal dysfunction receiving infusions of MIVACRON for an average of 1 to 2 hours; however, the duration may be longer and the rate of recovery may be slower following administration of MIVACRON in some patients with renal dysfunction. Table 5. Stereoisomer Pharmacokinetic Parameters* of Mivacurium in ASA Physical Status I-II Adult Patients with Normal Renal Function [Serum Creatinine less than or equal to 1 mg/dL], Patients with Mild to Moderate Renal Dysfunction [Serum Creatinine 1.3 to 2.7 mg/dL] and Patients with Severe Renal Dysfunction [Serum Creatinine greater than 6.2 mg/dL] During Opioid/Nitrous Oxide/Oxygen Anesthesia Parameter Isomer Normal Renal Function (n = 10) Mild to Moderate Renal Dysfunction (n = 8) Severe Renal Dysfunction (n = 7) Plasma Clearance (mL/min/kg) trans-trans isomer 54 (19 - 91) 49 (43 - 59) 53 (17 - 82) cis-trans isomer 97‡ (28 - 215) 93 (72 - 115) 110 (23 - 199) cis-cis isomer 4 (2.9 - 5.4) 2.5 (1.9 - 3.8) 2.8 (2.1 - 4.7) Volume of Distribution† (mL/kg) trans-trans isomer 179 (67 - 492) 243 (119 - 707) 238 (93 - 397) cis-trans isomer 303§ (97 - 776) 474 (284 - 908) 416\|\| (64 - 802) cis-cis isomer 287 (169 424) 323 (254 - 473) 276 (213 - 351) Half-life (min) trans-trans isomer 2.6 (1 - 6.8) 3.6 (1.7 - 10.7) 3.2 (1.6 - 4.1) cis-trans 2.3§ (0.7 - 5.2) 3.7 (2.2 - 6.9) 2.6\|\| (1.2 - 5.1) dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda isomer cis-cis isomer 52 (28 - 80) 90 (66 - 103) 73 (34 - 111) 25% to 75% Recovery Index (min) 10.8¶ (7.3 19.9) 9.2 (5.2 - 13.8) 10.3§ (4.1 - 14.2) * Values shown are mean (range). † Volume of distribution during the terminal elimination phase. ‡ n = 9 § n = 8 \|\| n = 6 ¶ n = 11 Patients with Hepatic Disease The clinically effective duration of action of 0.15 mg/kg MIVACRON was three times longer in eight patients with end-stage liver disease (undergoing liver transplantation) than in eight healthy patients and is likely related to the markedly decreased plasma cholinesterase activity (30% of healthy patient values) which could decrease the clearance of the trans-trans and cis-trans isomers (see PRECAUTIONS - Reduced Plasma Cholinesterase Activity). A separate study compared the pharmacokinetics and pharmacodynamics of mivacurium in patients with mild or moderate cirrhosis to healthy adults with normal hepatic function (Table 6). Although the number of patients in each group is small, the CL values of the more potent isomers, trans-trans and cis-trans, are lower in patients with mild to moderate cirrhosis as expected based on the marked decreases in plasma cholinesterase activity in this population (see PRECAUTIONS - Reduced Plasma Cholinesterase Activity). Table 6. Pharmacokinetic and Pharmacodynamic Parameters* of Mivacurium in ASA Physical Status I-II Patients and In Patients with Mild or Moderate Cirrhosis During Opioid/Nitrous Oxide/Oxygen Anesthesia Degree of Hepatic Failure Parameter Isomer Normal Hepatic Function (n = 10) Mild Cirrhosis (n = 5) Moderate Cirrhosis (n = 6) Plasma Clearance (mL/min/kg) trans-trans isomer 66 (34 - 99) 43 (22 - 64) 31 (11 - 66) cis-trans isomer 124‡ (57 - 218) 73 (34 - 111) 52 (18 - 128) cis-cis isomer 8.6 (4.5 - 13.3) 8.6 (4.5 - 16.7) 5.6 (3.5 - 9.7) Volume of Distribution† (mL/kg) trans-trans isomer 204‡ (94 - 269) 221 (118 - 457) 191 (74 - 273) cis-trans isomer 201‡ (89 - 411) 152 (102 - 256) 111 (56 - 164) cis-cis isomer§ – – – Half-life (min) trans-trans isomer 2.4‡ (1.3 - 3.9) 3.7 (1.7 - 5.1) 5.3 (1.7 - 8.5) cis-trans isomer 1.2‡ (0.6 - 2.1) 1.6 (1 - 2.1) 1.9 (0.9 - 3) cis-cis isomer§ – – – dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25% to 75% Recovery Index (min) 7.3 (4.7 - 9.6) 9.5 (5.7 - 12.3) 16.4 (6.3 - 26.2) * Values shown are mean (range). † Volume of distribution during the terminal elimination phase. ‡ n = 9 § Not available. Individualization of Dosages Doses of MIVACRON should be individualized and a peripheral nerve stimulator should be used to measure neuromuscular function during administration of MIVACRON in order to monitor drug effect, determine the need for additional doses, and confirm recovery from neuromuscular block. Based on the known actions of MIVACRON (a mixture of three stereoisomers) and other neuromuscular blocking agents, the following factors should be considered when administering MIVACRON: Renal or Hepatic Impairment A dose of 0.15 mg/kg MIVACRON is recommended for facilitation of tracheal intubation in patients with renal or hepatic impairment. However, the clinically effective duration of block produced by this dose may be about 1.5 times longer in patients with end-stage kidney disease and about 3 times longer in patients with end-stage liver disease than in patients with normal renal and hepatic function. Infusion rates should be decreased by as much as 50% in patients with hepatic disease depending on the degree of hepatic impairment (see PRECAUTIONS Renal and Hepatic Disease). No infusion rate adjustments are necessary in patients with renal impairment. Reduced Plasma Cholinesterase Activity The possibility of prolonged neuromuscular block following administration of MIVACRON must be considered in patients with reduced plasma cholinesterase (pseudocholinesterase) activity. MIVACRON should be used with great caution, if at all, in patients known or suspected of being homozygous for the atypical plasma cholinesterase gene (see WARNINGS). Doses of 0.03 mg/kg produced complete neuromuscular block for 26 to 128 minutes in three such patients; thus initial doses greater than 0.03 mg/kg are not recommended in homozygous patients. Infusions of MIVACRON are not recommended in homozygous patients. MIVACRON has been used safely in patients heterozygous for the atypical plasma cholinesterase gene and in genotypically normal patients with reduced plasma cholinesterase activity. After an initial dose of 0.15 mg/kg MIVACRON, the clinically effective duration of block in heterozygous patients may be approximately 10 minutes longer than in patients with normal genotype and normal plasma cholinesterase activity. Lower infusion rates of MIVACRON are recommended in these patients (see PRECAUTIONS - Reduced Plasma Cholinesterase Activity). Drugs or Conditions Causing Potentiation of or Resistance to Neuromuscular Block As with other neuromuscular blocking agents, MIVACRON may have profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis. In these or other patients in whom potentiation of neuromuscular dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda block or difficulty with reversal may be anticipated, the initial dose should be decreased. A test dose of not more than 0.015 to 0.02 mg/kg, which represents the lower end of the dose-response curve for MIVACRON, is recommended in such patients (see PRECAUTIONS - General). The neuromuscular blocking action of MIVACRON is potentiated by isoflurane or enflurane anesthesia. Recommended initial doses of MIVACRON (see DOSAGE AND ADMINISTRATION) may be used for intubation prior to the administration of these agents. If MIVACRON is first administered after establishment of stable-state isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen to achieve 1.25 MAC), the initial dose of MIVACRON should be reduced by as much as 25%, and the infusion rate reduced by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking action of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. The use of halothane requires no adjustment of the initial dose of MIVACRON, but may prolong the duration of action and decrease the average infusion rate by as much as 20% (see PRECAUTIONS - Drug Interactions). When MIVACRON is administered to patients receiving certain antibiotics, magnesium salts, lithium, local anesthetics, procainamide and quinidine, longer durations of neuromuscular block may be expected and infusion requirements may be lower (see PRECAUTIONS - Drug Interactions). When MIVACRON is administered to patients chronically receiving phenytoin or carbamazepine, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher (see PRECAUTIONS - Drug Interactions). Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of MIVACRON. No data are available in such patients and no dosing recommendations can be made (see PRECAUTIONS - General). Burns While patients with burns are known to develop resistance to nondepolarizing neuromuscular blocking agents, they may also have reduced plasma cholinesterase activity. Consequently, in these patients, a test dose of not more than 0.015 to 0.02 mg/kg MIVACRON is recommended, followed by additional appropriate dosing guided by the use of a neuromuscular block monitor (see PRECAUTIONS - General). Cardiovascular Disease In patients with clinically significant cardiovascular disease, the initial dose of MIVACRON should be 0.15 mg/kg or less, administered over 60 seconds (see CLINICAL PHARMACOLOGY - Hemodynamics subsection and PRECAUTIONS - General). Obesity Obese patients (patients weighing greater than or equal to 30% more than their ideal body weight) dosed on the basis of actual body weight, thereby receiving a larger dose than if dosed on the basis of ideal body weight, had a greater probability of experiencing a decrease of greater than or equal to 30% in MAP (see CLINICAL PHARMACOLOGY - Hemodynamics subsection and PRECAUTIONS - General). Therefore, in obese patients, the initial dose should be determined using the patient's ideal body weight (IBW), according to the following formulae: dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Men: IBW in kg = (106 + [6 x inches in height above 5 feet])/2.2 Women: IBW in kg = (100 + [5 x inches in height above 5 feet])/2.2 Allergy and Sensitivity In patients with any history suggestive of a greater sensitivity to the release of histamine or related mediators (e.g., asthma), the initial dose of MIVACRON should be 0.15 mg/kg or less, administered over 60 seconds (see PRECAUTIONS - General). INDICATIONS AND USAGE MIVACRON is a short-acting neuromuscular blocking agent indicated for inpatients and outpatients, as an adjunct to general anesthesia, to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. CONTRAINDICATIONS MIVACRON is contraindicated in patients with known hypersensitivity to the product and its components. WARNINGS Anaphylaxis Severe anaphylactic reactions to neuromuscular blocking agents, including MIVACRON, have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non depolarizing, has been reported in this class of drugs. Administration MIVACRON should be administered in carefully adjusted dosage by or under the supervision of experienced clinicians who are familiar with the drug's actions and the possible complications of its use. The drug should not be administered unless personnel and facilities for resuscitation and life support (tracheal intubation, artificial ventilation, oxygen therapy), and an antagonist of MIVACRON are immediately available. It is recommended that a peripheral nerve stimulator be used to measure neuromuscular function during the administration of MIVACRON in order to monitor drug effect, determine the need for additional drug, and confirm recovery from neuromuscular block. MIVACRON has no known effect on consciousness, pain threshold, or cerebration. To avoid distress to the patient, neuromuscular block should not be induced before unconsciousness. dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MIVACRON is metabolized by plasma cholinesterase and should be used with great caution, if at all, in patients known to be or suspected of being homozygous for the atypical plasma cholinesterase gene. MIVACRON Injection is acidic (pH 3.5 to 5) and may not be compatible with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions). PRECAUTIONS General Although MIVACRON (a mixture of three stereoisomers) is not a potent histamine releaser, the possibility of substantial histamine release must be considered. Release of histamine is related to the dose and speed of injection. Caution should be exercised in administering MIVACRON to patients with clinically significant cardiovascular disease and patients with any history suggesting a greater sensitivity to the release of histamine or related mediators (e.g., asthma). In such patients, the initial dose of MIVACRON should be 0.15 mg/kg or less, administered over 60 seconds; assurance of adequate hydration and careful monitoring of hemodynamic status are important (see CLINICAL PHARMACOLOGY - Hemodynamics and Individualization of Dosages). Obese patients may be more likely to experience clinically significant transient decreases in MAP than non-obese patients when the dose of MIVACRON is based on actual rather than ideal body weight. Therefore, in obese patients, the initial dose should be determined using the patient's ideal body weight (see CLINICAL PHARMACOLOGY - Hemodynamics and Individualization of Dosages). Recommended doses of MIVACRON have no clinically significant effects on heart rate; therefore, MIVACRON will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation. Neuromuscular blocking agents may have a profound effect in patients with neuromuscular diseases (e.g., myasthenia gravis and the myasthenic syndrome). In these and other conditions in which prolonged neuromuscular block is a possibility (e.g., carcinomatosis), the use of a peripheral nerve stimulator and a dose of not more than 0.015 to 0.02 mg/kg MIVACRON is recommended to assess the level of neuromuscular block and to monitor dosage requirements (see CLINICAL PHARMACOLOGY - Individualization of Dosages). MIVACRON has not been studied in patients with burns. Resistance to nondepolarizing neuromuscular blocking agents may develop in patients with burns, depending upon the time elapsed since the injury and the size of the burn. Patients with burns may have reduced plasma cholinesterase activity which may offset this resistance (see CLINICAL PHARMACOLOGY Individualization of Dosages). Acid-base and/or serum electrolyte abnormalities may potentiate or antagonize the action of neuromuscular blocking agents. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy (see CLINICAL PHARMACOLOGY - Individualization of Dosages). dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda No data are available to support the use of MIVACRON by intramuscular injection. Allergic Reactions Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including MIVACRON have been reported (see CONTRAINDICATIONS). Renal and Hepatic Disease The possibility of prolonged neuromuscular block must be considered when MIVACRON is used in patients with renal or hepatic disease (see CLINICAL PHARMACOLOGY - Pharmacokinetics). Most patients with chronic hepatic disease such as hepatitis, liver abscess, and cirrhosis of the liver exhibit a marked reduction in plasma cholinesterase activity. Patients with acute or chronic renal disease may also show a reduction in plasma cholinesterase activity (see CLINICAL PHARMACOLOGY - Individualization of Dosages). Reduced Plasma Cholinesterase Activity The possibility of prolonged neuromuscular block following administration of MIVACRON must be considered in patients with reduced plasma cholinesterase (pseudocholinesterase) activity. Plasma cholinesterase activity may be diminished in the presence of genetic abnormalities of plasma cholinesterase (e.g., patients heterozygous or homozygous for the atypical plasma cholinesterase gene), pregnancy, liver or kidney disease, malignant tumors, infections, burns, anemia, decompensated heart disease, peptic ulcer, or myxedema. Plasma cholinesterase activity may also be diminished by chronic administration of oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors and by irreversible inhibitors of plasma cholinesterase (e.g., organophosphate insecticides, echothiophate, and certain antineoplastic drugs). MIVACRON has been used safely in patients heterozygous for the atypical plasma cholinesterase gene. At doses of 0.1 to 0.2 mg/kg MIVACRON, the clinically effective duration of action was 8 minutes to 11 minutes longer in patients heterozygous for the atypical gene than in genotypically normal patients. As with succinylcholine, patients homozygous for the atypical plasma cholinesterase gene (one in 2500 patients) are extremely sensitive to the neuromuscular blocking effect of MIVACRON. In three such adult patients, a small dose of 0.03 mg/kg (approximately the ED10-20 in genotypically normal patients) produced complete neuromuscular block for 26 to 128 minutes. Once spontaneous recovery had begun, neuromuscular block in these patients was antagonized with conventional doses of neostigmine. One adult patient, who was homozygous for the atypical plasma cholinesterase gene, received a dose of 0.18 mg/kg MIVACRON and exhibited complete neuromuscular block for about 4 hours. Response to post-tetanic stimulation was present after 4 hours, all four responses to train-of-four stimulation were present after 6 hours, and the patient was extubated after 8 hours. Reversal was not attempted in this patient. dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Malignant Hyperthermia (MH) In a study of MH-susceptible pigs, MIVACRON did not trigger MH. MIVACRON has not been studied in MH-susceptible patients. Because MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient undergoing general anesthesia. Long-Term Use in the Intensive Care Unit (ICU) No data are available on the long-term use of MIVACRON in patients undergoing mechanical ventilation in the ICU. Drug Interactions Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 MAC) decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY - Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50, but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase (see PRECAUTIONS Reduced Plasma Cholinesterase Activity subsection). Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and fertility studies have not been performed. MIVACRON was evaluated in a battery of four short-term mutagenicity tests. It was non-mutagenic in the Ames Salmonella assay, the mouse lymphoma assay, the human lymphocyte assay, and the in vivo rat bone marrow cytogenetic assay. Pregnancy Teratogenic Effects Pregnancy Category C Teratology testing in nonventilated pregnant rats and mice treated subcutaneously with maximum subparalyzing doses of MIVACRON revealed no maternal or fetal toxicity or teratogenic effects. There are no adequate and well-controlled studies of MIVACRON in pregnant women. Because animal studies are not always predictive of human response, and the doses used were subparalyzing, MIVACRON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The use of MIVACRON during labor, vaginal delivery, or cesarean section has not been studied in humans and it is not known whether MIVACRON administered to the mother has effects on the fetus. Doses of 0.08 and 0.2 mg/kg MIVACRON given to female beagles undergoing cesarean section resulted in negligible levels of the stereoisomers in MIVACRON in umbilical vessel blood of neonates and no deleterious effects on the puppies. Nursing Mothers It is not known whether any of the stereoisomers of mivacurium are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised following administration of MIVACRON to a nursing woman. Pediatric Use MIVACRON has not been studied in pediatric patients below the age of 2 years (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION for clinical experience and recommendations for use in children 2 to 12 years of age). Geriatric Use MIVACRON was safely administered during clinical trials to 64 geriatric (greater than or equal to 65 years) patients, including 31 patients with significant cardiovascular disease (see PRECAUTIONS - General subsection). In general, the clearances of MIVACRON are most likely lower, the duration may be longer, the rate of recovery may be slower, therefore, MIVACRON requirements may be lower in geriatric patients (see CLINICAL PHARMACOLOGY - Special Populations - Geriatric Patients). dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Observed in Clinical Trials MIVACRON (a mixture of three stereoisomers) was well tolerated during extensive clinical trials in inpatients and outpatients. Prolonged neuromuscular block, which is an important adverse experience associated with neuromuscular blocking agents as a class, was reported as an adverse experience in three of 2074 patients administered MIVACRON. The most commonly reported adverse experience following the administration of MIVACRON was transient, dose- dependent cutaneous flushing about the face, neck, and/or chest. Flushing was most frequently noted after the initial dose of MIVACRON and was reported in about 25% of adult patients who received 0.15 mg/kg MIVACRON over 5 to 15 seconds. When present, flushing typically began within 1 to 2 minutes after the dose of MIVACRON and lasted for 3 to 5 minutes. Of 105 patients who experienced flushing after 0.15 mg/kg MIVACRON, two patients also experienced mild hypotension that was not treated, and one patient experienced moderate wheezing that was successfully treated. Overall, hypotension was infrequently reported as an adverse experience in the clinical trials of MIVACRON. One of 332 (0.3%) healthy adults who received 0.15 mg/kg MIVACRON over 5 to 15 seconds and none of 37 cardiac surgery patients who received 0.15 mg/kg MIVACRON over 60 seconds were treated for a decrease in blood pressure in association with the administration of MIVACRON. One to two percent of healthy adults given greater than or equal to 0.2 mg/kg MIVACRON over 5 to 15 seconds, 2% to 3% of healthy adults given 0.2 mg/kg over 30 seconds, none of 100 healthy adults given 0.25 mg/kg as a divided dose (0.15 mg/kg followed in 30 seconds by 0.1 mg/kg), and 2% to 4% of cardiac surgery patients given greater than or equal to 0.2 mg/kg over 60 seconds were treated for a decrease in blood pressure. None of the 63 children who received the recommended dose of 0.2 mg/kg MIVACRON was treated for a decrease in blood pressure in association with the administration of MIVACRON. The following adverse experiences were reported in patients administered MIVACRON (all events judged by investigators during the clinical trials to have a possible causal relationship): Incidence Greater Than 1% Cardiovascular Flushing (16%) Incidence Less Than 1% Cardiovascular Hypotension, tachycardia, bradycardia, cardiac arrhythmia, phlebitis Respiratory Bronchospasm, wheezing, hypoxemia Dermatological Rash, urticaria, erythema, injection site reaction Nonspecific dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Prolonged drug effect Neurologic Dizziness Musculoskeletal Muscle spasms Observed in Clinical Practice Based on initial clinical practice experience in patients who received MIVACRON, spontaneously reported adverse events are uncommon. Some of these events occurred at recommended doses and required treatment. Anaphylaxis/Anaphylactoid Reactions: From post-marketing surveillance, MIVACRON has been associated with reports of anaphylactic/anaphylactoid reactions which in some cases have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see WARNINGS and PRECAUTIONS). In some of these reports, sensitivity to MIVACRON was confirmed using skin test procedures. Other adverse reaction data from clinical practice are insufficient to establish a causal relationship or to support an estimate of their incidence. These adverse events include: Musculoskeletal Diminished drug effect, prolonged drug effect Cardiovascular Hypotension (rarely severe), flushing Respiratory Bronchospasm Integumentary Rash OVERDOSAGE Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway and controlled ventilation until recovery of normal neuromuscular function is assured. Once evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent (e.g., neostigmine, edrophonium) in conjunction with an appropriate anticholinergic agent (see Antagonism of Neuromuscular Block subsection below). Overdosage may increase the risk of hemodynamic side effects, especially decreases in blood pressure. If needed, cardiovascular support may be provided by proper positioning of the patient, fluid administration, and/or vasopressor agent administration. dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Antagonism of Neuromuscular Block Antagonists (such as neostigmine) should not be administered when complete neuromuscular block is evident or suspected. The use of a peripheral nerve stimulator to evaluate recovery and antagonism of neuromuscular block is recommended. Administration of 0.03 to 0.064 mg/kg neostigmine or 0.5 mg/kg edrophonium at approximately 10% recovery from neuromuscular block (range: 1 to 15) produced 95% recovery of the muscle twitch response and a T4/T1 ratio greater than or equal to 75% in about 10 minutes. The times from 25% recovery of the muscle twitch response to T4/T1 ratio greater than or equal to 75% following these doses of antagonists averaged about 7 to 9 minutes. In comparison, average times for spontaneous recovery from 25% to T4/T1 greater than or equal to 75% were 12 to 13 minutes. Patients administered antagonists should be evaluated for adequate clinical evidence of antagonism, e.g., 5-second head lift and grip strength. Ventilation must be supported until no longer required. Antagonism may be delayed in the presence of debilitation, carcinomatosis, and the concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular block or separately cause respiratory depression (see PRECAUTIONS - Drug Interactions). Under such circumstances the management is the same as that of prolonged neuromuscular block (see OVERDOSAGE). DOSAGE AND ADMINISTRATION MIVACRON SHOULD ONLY BE ADMINISTERED INTRAVENOUSLY. The dosage information provided below is intended as a guide only. Doses of MIVACRON should be individualized (see CLINICAL PHARMACOLOGY - Individualization of Dosages). Factors that may warrant dosage adjustment include but may not be limited to: the presence of significant kidney, liver, or cardiovascular disease, obesity (patients weighing greater than or equal to 30% more than ideal body weight for height), asthma, reduction in plasma cholinesterase activity, and the presence of inhalational anesthetic agents. When using MIVACRON or other neuromuscular blocking agents to facilitate tracheal intubation, it is important to recognize that the most important factors affecting intubation are the depth of general anesthesia and the level of neuromuscular block. Satisfactory intubating conditions can usually be achieved before complete neuromuscular block is attained if there is adequate anesthesia. The use of a peripheral nerve stimulator will permit the most advantageous use of MIVACRON, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery. When using a stimulator to monitor onset of neuromuscular block, clinical studies have shown that all four twitches of the train-of-four response may be present, with little or no fade, at the times recommended for intubation. Therefore, as with other neuromuscular blocking agents, it is important to use other criteria, such as clinical evaluation of the status of relaxation of jaw muscles and vocal cords, in conjunction with peripheral muscle twitch monitoring, to guide the appropriate time of intubation. dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The onset of conditions suitable for tracheal intubation occurs earlier after a conventional intubating dose of succinylcholine than after recommended doses of MIVACRON. Adults Initial Doses Doses of 0.15 mg/kg administered over 5 to 15 seconds, 0.2 mg/kg administered over 30 seconds, or 0.25 mg/kg administered in divided doses (0.15 mg/kg followed in 30 seconds by 0.1 mg/kg) are recommended for facilitation of tracheal intubation for most patients (see Table 7). Table 7. Recommended Initial Dosing Regimens for Adults Dosing Paradigm* Anesthetic Induction Technique Studied Time to Generally Good-to- Excellent Intubating Conditions 0.15 mg/kg, intravenous (over 5 to 15 sec) Thiopental/opioid/N2O/O2 or propofol/opioid 2.5 to 3 min after completion of dose 0.2 mg/kg, intravenous (over 30 sec) Thiopental/opioid/N2O/O2 or propofol/opioid 2 to 2.5 min after completion of dose 0.25 mg/kg, . intravenous (0.15 mg/kg followed in 30 sec by 0.1 mg/kg) Propofol/opioid 1.5 to 2 min after completion of 0.15 mg/kg dose * Dosing instituted after induction of adequate general anesthesia. The purpose of slowed or divided dosing of MIVACRON at doses above 0.15 mg/kg is to minimize the transient decreases in blood pressure observed in some patients given these doses over 5 to 15 seconds (see CLINICAL PHARMACOLOGY, PRECAUTIONS, and ADVERSE REACTIONS). The quality of intubation conditions does not significantly differ for the times and doses of MIVACRON recommended in Table 7, but the onset of suitable intubation conditions may be reached earlier with higher doses. The choice of a particular dose and regimen should be based on individual circumstances and patient requirements (see CLINICAL PHARMACOLOGY - Individualization of Dosages). In patients with clinically significant cardiovascular disease and in patients with any history suggesting a greater sensitivity to the release of histamine or other mediators (e.g., asthma), the dose of MIVACRON should be 0.15 mg/kg or less, administered over 60 seconds (see PRECAUTIONS). No data are available on the use of doses of MIVACRON above 0.15 mg/kg in patients with clinically significant kidney or liver disease. Clinically effective neuromuscular block may be expected to last for 15 to 20 minutes (range: 9 to 38 minutes) and spontaneous recovery may be expected to be 95% complete in 25 to 30 minutes (range: 16 to 41 minutes) following 0.15 mg/kg MIVACRON administered to patients receiving opioid/nitrous oxide/oxygen anesthesia. The expected duration of clinically effective block and time to 95% spontaneous recovery following 0.2 mg/kg MIVACRON are approximately 20 and 30 minutes, respectively, and following 0.25 mg/kg MIVACRON are dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda approximately 25 and 35 minutes. Initiation of maintenance dosing during opioid/nitrous oxide/oxygen anesthesia is generally required approximately 15, 20 and 25 minutes following initial doses of 0.15 mg/kg, 0.2 mg/kg, and 0.25 mg/kg MIVACRON, respectively (see Table 1). Maintenance doses of 0.1 mg/kg each provide approximately 15 minutes of additional clinically effective block. For shorter or longer durations of action, smaller or larger maintenance doses may be administered. The neuromuscular blocking action of MIVACRON is potentiated by isoflurane or enflurane anesthesia. Recommended initial doses of MIVACRON may be used to facilitate tracheal intubation prior to the administration of these agents; however, if MIVACRON is first administered after establishment of stable-state isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen to achieve 1.25 MAC), the initial dose of MIVACRON may be reduced by as much as 25%. Greater reductions in the dose of MIVACRON may be required with higher concentrations of enflurane or isoflurane. With halothane, which has only a minimal potentiating effect on MIVACRON, a smaller dosage reduction may be considered. Continuous Infusion Continuous infusion of MIVACRON may be used to maintain neuromuscular block. Upon early evidence of spontaneous recovery from an initial dose, an initial infusion rate of 9 to 10 mcg/kg/min is recommended. If continuous infusion is initiated simultaneously with the administration of an initial dose, a lower initial infusion rate should be used (e.g., 4 mcg/kg/min). In either case, the initial infusion rate should be adjusted according to the response to peripheral nerve stimulation and to clinical criteria. On average, an infusion rate of 5 to 7 mcg/kg/min (range: 1 to 15 mcg/kg/min) may be expected to maintain neuromuscular block within the range of 89% to 99% for extended periods in adults receiving opioid/nitrous oxide/oxygen anesthesia. In some patients, particularly those with higher infusion requirements (greater than 8 mcg/kg/min) during the first 30 minutes, the infusion rate required to maintain 89% to 99% T1 suppression may decrease gradually (by greater than or equal to 30%) with time over a 4- to 6 hour period of infusion (see CLINICAL PHARMACOLOGY - Pharmacodynamics). Reduction of the infusion rate by up to 35% to 40% should be considered when MIVACRON is administered during stable-state conditions of isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen to achieve 1.25 MAC). Greater reductions in the infusion rate of MIVACRON may be required with greater concentrations of enflurane or isoflurane. With halothane, smaller reductions in infusion rate may be required. Children Initial Doses Dosage requirements for MIVACRON on a mg/kg basis are higher in children than in adults. Onset and recovery of neuromuscular block occur more rapidly in children than in adults (see CLINICAL PHARMACOLOGY). The recommended dose of MIVACRON for facilitating tracheal intubation in children 2 to 12 years of age is 0.2 mg/kg administered over 5 to 15 seconds. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.2 mg/kg of MIVACRON produces maximum neuromuscular block in an average of 1.9 minutes (range: 1.3 to 3.3 minutes) and clinically effective block for 10 minutes (range: 6 to 15 minutes). Maintenance doses are generally dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda required more frequently in children than in adults. Administration of doses of MIVACRON above the recommended range (greater than 0.2 mg/kg) is associated with transient decreases in MAP in some children (see CLINICAL PHARMACOLOGY - Hemodynamics). MIVACRON has not been studied in pediatric patients below the age of 2 years. Continuous Infusion Children require higher infusion rates of MIVACRON than adults. During opioid/nitrous oxide/oxygen anesthesia, the infusion rate required to maintain 89% to 99% neuromuscular block averages 14 mcg/kg/min (range: 5 to 31 mcg/kg/min). The principles for infusion of MIVACRON in adults are also applicable to children (see above). Infusion Rate Tables For adults and children the amount of infusion solution required per hour depends upon the clinical requirements of the patient, the concentration of MIVACRON in the infusion solution, and the patient's weight. The contribution of the infusion solution to the fluid requirements of the patient must be considered. Table 8 provides guidelines for delivery in mL/hr (equivalent to microdrops/min when 60 microdrops = 1 mL) of MIVACRON Injection (2 mg/mL). Table 8. Infusion Rates for Maintenance of Neuromuscular Block During Opioid/Nitrous Oxide/Oxygen Anesthesia Using MIVACRON Injection (2 mg/mL) Drug Delivery Rate (mcg/kg/min) 4 5 6 7 8 10 14 16 18 20 Patient Weight (kg) Infusion Delivery Rate (mL/hr) 10 1.2 1.5 1.8 2.1 2.4 3 4.2 4.8 5.4 6 15 1.8 2.3 2.7 3.2 3.6 4.5 6.3 7.2 8.1 9 20 2.4 3 3.6 4.2 4.8 6 8.4 9.6 10.8 12 25 3 3.8 4.5 5.3 6 7.5 10.5 12 13.5 15 35 4.2 5.3 6.3 7.4 8.4 10.5 14.7 16.8 18.9 21 50 6 7.5 9 10.5 12 15 21 24 27 30 60 7.2 9 10.8 12.6 14.4 18 25.2 28.8 32.4 36 70 8.4 10.5 12.6 14.7 16.8 21 29.4 33.6 37.8 42 80 9.6 12 14.4 16.8 19.2 24 33.6 38.4 43.2 48 90 10.8 13.5 16.2 18.9 21.6 27 37.8 43.2 48.6 54 100 12 15 18 21 24 30 42 48 54 60 MIVACRON Injection Compatibility and Admixtures Y-site Administration MIVACRON Injection may not be compatible with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions). Studies have shown that MIVACRON Injection is compatible with: • 5% Dextrose Injection, USP dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • 0.9% Sodium Chloride Injection, USP • 5% Dextrose and 0.9% Sodium Chloride Injection, USP • Lactated Ringer's Injection, USP • 5% Dextrose in Lactated Ringer's Injection • Sufenta® (sufentanil citrate) Injection, diluted as directed • Alfenta® (alfentanil hydrochloride) Injection, diluted as directed • Sublimaze® (fentanyl citrate) Injection, diluted as directed • Versed® (midazolam hydrochloride) Injection, diluted as directed • Inapsine® (droperidol) Injection, diluted as directed Compatibility studies with other parenteral products have not been conducted. Dilution Stability MIVACRON Injection diluted to 0.5 mg mivacurium per mL in 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP, 0.9% Sodium Chloride Injection, USP, Lactated Ringer's Injection, USP, or 5% Dextrose in Lactated Ringer's Injection is physically and chemically stable when stored in PVC (polyvinylchloride) bags at 5° to 25°C (41° to 77°F) for up to 24 hours. Aseptic techniques should be used to prepare the diluted product. Admixtures of MIVACRON should be prepared for single patient use only and used within 24 hours of preparation. The unused portion of diluted MIVACRON should be discarded after each case. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are not clear and colorless should not be used. HOW SUPPLIED MIVACRON Injection, 2 mg mivacurium in each mL. List Fill Container Quantity NDC# 4365 5 mL Single-Dose Fliptop Vial 10 per Carton NDC 0074-4365-05 4365 10 mL Single-Dose Fliptop Vial 10 per Carton NDC 0074-4365-10 STORAGE Store MIVACRON Injection at 25°C (77°F). Excursions permitted between 15° - 30°C (59° 86°F). DO NOT FREEZE. MIVACRON is a registered trademark of GlaxoSmithKline, licensed for use by AbbVie Inc. Sufenta, Alfenta, Sublimaze, Versed, and Inapsine are not trademarks of AbbVie Inc. ©AbbVie Inc. 2014 Manufactured for AbbVie Inc. North Chicago, IL 60064, USA dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda XXXX 2015 dn2981-proposed-mivacron-uspi-0035-2015-jan-23 Reference ID: 3694923 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:44.673522	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020098s018lbl.pdf', 'application_number': 20098, 'submission_type': 'SUPPL ', 'submission_number': 18}
12,212	1 PV 5321 DPP PROZAC® FLUOXETINE CAPSULES, USP FLUOXETINE ORAL SOLUTION, USP WARNING Suicidality in Children and Adolescents — Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Prozac or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Prozac is approved for use in pediatric patients with MDD and obsessive compulsive disorder (OCD). (See WARNINGS and PRECAUTIONS, Pediatric Use.) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. DESCRIPTION Prozac® (fluoxetine capsules, USP and fluoxetine oral solution, USP) is a psychotropic drug for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α- trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NOy HCl. Its molecular weight is 345.79. The structural formula is: Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg Pulvules also contain FD&C Blue No. 1, and the 40-mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 μmol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. Prozac Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 μmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients. CLINICAL PHARMACOLOGY Pharmacodynamics The antidepressant, antiobsessive compulsive, and antibulimic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. Absorption, Distribution, Metabolism, and Excretion Systemic bioavailability — In man, following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations. Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS). Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical issues related to metabolism/elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine’s clinical use. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Variability in metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see Drug Interactions under PRECAUTIONS). Accumulation and slow elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of Prozac. Weekly dosing — Administration of Prozac Weekly once weekly results in increased fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of fluoxetine are in the range of the average concentration for 20-mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20-mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared with the once-daily regimen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Cmax for fluoxetine following the 90-mg dose was approximately 1.7-fold higher than the Cmax value for the established 20-mg once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90-mg once-weekly dose and the last 20-mg once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better to separate the first 90-mg weekly dose and the last 20-mg once-daily dose by 1 week (see DOSAGE AND ADMINISTRATION). Liver disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Renal disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see Use in Patients with Concomitant Illness under PRECAUTIONS and DOSAGE AND ADMINISTRATION). Age Geriatric pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events was observed in those elderly patients. Pediatric pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with major depressive disorder or obsessive compulsive disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with major depressive disorder. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. CLINICAL TRIALS Major Depressive Disorder Daily Dosing Adult — The efficacy of Prozac for the treatment of patients with major depressive disorder (≥ 18 years of age) has been studied in 5- and 6-week placebo-controlled trials. Prozac was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Prozac was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. Two 6-week controlled studies (N=671, randomized) comparing Prozac 20 mg and placebo have shown Prozac 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with major depressive disorder. In these studies, Prozac produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. Prozac was well tolerated and the rate of treatment discontinuations due to adverse events did not differ between Prozac (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on Prozac 20 mg/day. These patients (N=298) were randomized to continuation on double-blind Prozac 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major depressive disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking Prozac compared with those on placebo. Pediatric (children and adolescents) — The efficacy of Prozac 20 mg/day for the treatment of major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) has been studied in two 8- to 9-week placebo-controlled clinical trials. In both studies independently, Prozac produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Weekly dosing for maintenance/continuation treatment A longer-term study was conducted involving adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded (defined as having a modified HAMD-17 score of ≤9, a CGI-Severity rating of ≤2, and no longer meeting criteria for major depressive disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with Prozac 20 mg once daily. These patients were randomized to double-blind, once-weekly continuation treatment with Prozac Weekly, Prozac 20 mg once daily, or placebo. Prozac Weekly once weekly and Prozac 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. However, the equivalence of these 2 treatments during continuation therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Obsessive Compulsive Disorder Adult — The effectiveness of Prozac for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed Prozac doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Prozac experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving Prozac experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Prozac Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD, patients received Prozac 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Prozac produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. Bulimia Nervosa The effectiveness of Prozac for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Prozac or placebo in the morning. Patients in the 16-week study received a fixed Prozac dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, Prozac 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 and persisted throughout each study. The Prozac-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between Prozac 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with Prozac 60 mg/day, were randomized to continuation of Prozac 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued Prozac 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. Panic Disorder The effectiveness of Prozac in the treatment of panic disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. Study 1 (N=180 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N=214 randomized) was a 12-week flexible-dose study. Prozac was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of Prozac-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively. INDICATIONS AND USAGE Major Depressive Disorder Prozac is indicated for the treatment of major depressive disorder. Adult — The efficacy of Prozac was established in 5- and 6-week trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of major depressive disorder (see CLINICAL TRIALS). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The effects of Prozac in hospitalized depressed patients have not been adequately studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 The efficacy of Prozac 20 mg once daily in maintaining a response in major depressive disorder for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in a placebo-controlled trial. The efficacy of Prozac Weekly once weekly in maintaining a response in major depressive disorder has been demonstrated in a placebo-controlled trial for up to 25 weeks following open-label acute treatment of 13 weeks with Prozac 20 mg daily for a total treatment of 38 weeks. However, it is unknown whether or not Prozac Weekly given on a once-weekly basis provides the same level of protection from relapse as that provided by Prozac 20 mg daily (see CLINICAL TRIALS). Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see CLINICAL TRIALS). The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should be reevaluated periodically. Obsessive Compulsive Disorder Adult — Prozac is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of Prozac was established in 13-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see CLINICAL TRIALS). OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. The effectiveness of Prozac in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Pediatric (children and adolescents) — The efficacy of Prozac in children and adolescents was established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in DSM-IV (see CLINICAL TRIALS). Bulimia Nervosa Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa. The efficacy of Prozac was established in 8- to 16-week trials for adult outpatients with moderate to severe bulimia nervosa, i.e., at least 3 bulimic episodes per week for 6 months (see CLINICAL TRIALS). The efficacy of Prozac 60 mg/day in maintaining a response, in patients with bulimia who responded during an 8-week acute treatment phase while taking Prozac 60 mg/day and were then observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Panic Disorder This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Prozac is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks, and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of Prozac was established in two 12-week clinical trials in patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL TRIALS). Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 or more of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear of losing control; 10) fear of dying; 11) paresthesias (numbness or tingling sensations); 12) chills or hot flashes. The effectiveness of Prozac in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use Prozac for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Prozac is contraindicated in patients known to be hypersensitive to it. Monoamine oxidase inhibitors — There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Prozac should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY)] should be allowed after stopping Prozac before starting an MAOI. Pimozide — Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS). Thioridazine — Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued (see WARNINGS). WARNINGS Clinical Worsening and Suicide Risk — Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Prozac, for a description of the risks of discontinuation of Prozac). Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Prozac should be written for the smallest quantity of capsules, or liquid This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. It should be noted that Prozac is approved in the pediatric population only for major depressive disorder and obsessive compulsive disorder. Screening Patients for Bipolar Disorder — A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Prozac is not approved for use in treating bipolar depression. Rash and Possibly Allergic Events — In US fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of Prozac, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Prozac should be discontinued. Serotonin Syndrome — The development of a potentially life-threatening serotonin syndrome may occur with Prozac treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Prozac with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and Drug Interactions under PRECAUTIONS). If concomitant treatment of Prozac with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Drug Interactions under PRECAUTIONS). The concomitant use of Prozac with serotonin precursors (such as tryptophan) is not recommended (see Drug Interactions under PRECAUTIONS). Potential Interaction with Thioridazine — In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS). Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS). PRECAUTIONS General Abnormal Bleeding — Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of Prozac with NSAIDs, aspirin, or other drugs that affect coagulation. Anxiety and Insomnia — In US placebo-controlled clinical trials for major depressive disorder, 12% to 16% of patients treated with Prozac and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Prozac and in 7% of patients treated with placebo. In US placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Prozac 60 mg and in 9% and 5% of patients treated with placebo. Among the most common adverse events associated with discontinuation (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in major depressive disorder) (see Table 3). Altered Appetite and Weight — Significant weight loss, especially in underweight depressed or bulimic patients may be an undesirable result of treatment with Prozac. In US placebo-controlled clinical trials for major depressive disorder, 11% of patients treated with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Prozac because of anorexia or weight loss (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Prozac because of anorexia (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Prozac 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy. Activation of Mania/Hypomania — In US placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with Prozac and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of major depressive disorder (see also Pediatric Use under PRECAUTIONS). In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Prozac and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania (see also Pediatric Use under PRECAUTIONS). Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when Prozac was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted. In two 6-week controlled studies in patients ≥60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration was 129 mmol/L. The observed decreases were not clinically significant. Seizures — In US placebo-controlled clinical trials for major depressive disorder, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patients treated with Prozac and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of major depressive disorder. Prozac should be introduced with care in patients with a history of seizures. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 The Long Elimination Half-Lives of Fluoxetine and its Metabolites — Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Use in Patients with Concomitant Illness — Clinical experience with Prozac in patients with concomitant systemic illness is limited. Caution is advisable in using Prozac in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received Prozac in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis. Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (see Renal disease under CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE AND ADMINISTRATION). In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred during therapy with Prozac, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with Prozac is instituted or discontinued. Interference with Cognitive and Motor Performance — Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Discontinuation of Treatment with Prozac — During marketing of Prozac and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Prozac. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION). Information for Patients This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Prozac and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Prozac. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Prozac. Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Prozac and triptans, tramadol or other serotonergic agents. Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected. Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs, or alcohol. Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast-feeding an infant. Patients should be advised to notify their physician if they develop a rash or hives. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs metabolized by CYP2D6 — Approximately 7% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme 2D6. Such individuals have been referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and TCAs. Many drugs, such as most drugs effective in the treatment of major depressive disorder, including fluoxetine and other selective uptake inhibitors of serotonin, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 are metabolized by this isoenzyme; thus, both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolizers. However, for fluoxetine and its metabolite, the sum of the plasma concentrations of the 4 active enantiomers is comparable between poor and extensive metabolizers (see Variability in metabolism under CLINICAL PHARMACOLOGY). Fluoxetine, like other agents that are metabolized by CYP2D6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble poor metabolizers. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS and WARNINGS). Drugs metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. CNS active drugs — The risk of using Prozac in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and Prozac. Concomitant use of Prozac and pimozide is contraindicated (see CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS and WARNINGS. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. Tryptophan — Five patients receiving Prozac in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. Monoamine oxidase inhibitors — See CONTRAINDICATIONS. Other drugs effective in the treatment of major depressive disorder — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY, and Drugs metabolized by CYP2D6 under Drug Interactions). Serotonergic drugs — Based on the mechanism of action of Prozac and the potential for serotonin syndrome, caution is advised when Prozac is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see Serotonin Syndrome under WARNINGS). The concomitant use of Prozac with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Prozac with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Serotonin Syndrome under WARNINGS). Potential effects of coadministration of drugs tightly bound to plasma proteins — Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY). Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.) — Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluoxetine. Warfarin — Altered anticoagulant effects, including increased bleeding, have been reported when fluoxetine is coadministered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped. Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. Carcinogenesis, Mutagenesis, Impairment of Fertility This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) was not observed. Carcinogenicity — The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity. Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use). Pregnancy Pregnancy Category C — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects — Neonates exposed to Prozac and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Monoamine oxidase inhibitors under CONTRAINDICATIONS). When treating a pregnant woman with Prozac during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Prozac on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. Pediatric Use The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 (see CLINICAL TRIALS). The efficacy of Prozac for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 (see CLINICAL TRIALS). The safety and effectiveness in pediatric patients <8 years of age in major depressive disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with major depressive disorder or OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY). The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS). Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. (See WARNINGS, Clinical Worsening and Suicide Risk.) Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain. Prozac is approved for use in pediatric patients with MDD and OCD (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Prozac in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use US fluoxetine clinical trials as of May 8, 1995 (10,782 patients) included 687 patients ≥ 65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established (see CLINICAL TRIALS). For pharmacokinetic information in geriatric patients, see Age under CLINICAL PHARMACOLOGY. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other SSRIs, fluoxetine has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS). ADVERSE REACTIONS Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered Prozac in panic clinical trials. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 1 enumerates the most common treatment-emergent adverse events associated with the use of Prozac (incidence of at least 5% for Prozac and at least twice that for placebo within at least 1 of the indications) for the treatment of major depressive disorder, OCD, and bulimia in US controlled clinical trials and panic disorder in US plus non-US controlled trials. Table 2 enumerates treatment-emergent adverse events that occurred in 2% or more patients treated with Prozac and with incidence greater than placebo who participated in US major depressive disorder, OCD, and bulimia controlled clinical trials and US plus non-US panic disorder controlled clinical trials. Table 2 provides combined data for the pool of studies that are provided separately by indication in Table 1. Table 1: Most Common Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Event Prozac (N=1728) Placebo (N=975) Prozac (N=266) Placebo (N=89) Prozac (N=450) Placebo (N=267) Prozac (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 -- 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence2 2 -- -- -- 7 -- 1 -- Abnormal ejaculation2 -- -- 7 -- 7 -- 2 1 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. 2 Denominator used was for males only (N=690 Prozac major depressive disorder; N=410 placebo major depressive disorder; N=116 Prozac OCD; N=43 placebo OCD; N=14 Prozac bulimia; N=1 placebo bulimia; N=162 Prozac panic; N=121 placebo panic). -- Incidence less than 1%. Table 2: Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Event2 Prozac (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 -- Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 1 Includes US data for major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US data for panic disorder clinical trials. 2 Included are events reported by at least 2% of patients taking Prozac, except the following events, which had an incidence on placebo ≥ Prozac (major depressive disorder, OCD, bulimia, and panic disorder combined): abdominal pain, abnormal dreams, accidental injury, back pain, cough increased, major depressive disorder (includes suicidal thoughts), dysmenorrhea, infection, myalgia, pain, paresthesia, pharyngitis, rhinitis, sinusitis. -- Incidence less than 1%. Associated with discontinuation in major depressive disorder, OCD, bulimia, and panic disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. Table 3: Most Common Adverse Events Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 -- -- Rash (1%) -- -- 1 Includes US major depressive disorder, OCD, bulimia, and panic disorder clinical trials, plus non-US panic disorder clinical trials. Other adverse events in pediatric patients (children and adolescents) — Treatment-emergent adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult studies, as shown in Tables 1 and 2. However, the following adverse events (excluding those which appear in the body or footnotes of Tables 1 and 2 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. The most common adverse event (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event associated with discontinuation was collected. Events observed in Prozac Weekly clinical trials — Treatment-emergent adverse events in clinical trials with Prozac Weekly were similar to the adverse events reported by patients in clinical trials with Prozac daily. In a placebo-controlled clinical trial, more patients taking Prozac Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking Prozac 20 mg daily (10% versus 5%, respectively). Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US major depressive disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Events Observed in Clinical Trials Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in US clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 1 or 2 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to Prozac use was considered remote; and (4) events occurring in only 1 patient treated with Prozac and which did not have a substantial probability of being acutely life-threatening. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients. Body as a Whole — Frequent: chest pain, chills; Infrequent: chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome1, photosensitivity reaction. Cardiovascular System — Frequent: hemorrhage, hypertension, palpitation; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System — Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema. Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional — Frequent: weight gain; Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis. Nervous System — Frequent: agitation, amnesia, confusion, emotional lability, sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder2, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor. Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System — Frequent: urinary frequency; Infrequent: abortion3, albuminuria, amenorrhea3, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation3, fibrocystic breast3, hematuria, leukorrhea3, menorrhagia3, metrorrhagia3, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage3; Rare: breast engorgement, glycosuria, hypomenorrhea3, kidney pain, oliguria, priapism3, uterine hemorrhage3, uterine fibroids enlarged3. 1 Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. 2 Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. 3 Adjusted for gender. Postintroduction Reports Voluntary reports of adverse events temporally associated with Prozac that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors. DRUG ABUSE AND DEPENDENCE Controlled substance class — Prozac is not a controlled substance. Physical and psychological dependence — Prozac has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Prozac (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope. Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management of Overdose). Management of Overdose Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS). Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). DOSAGE AND ADMINISTRATION Major Depressive Disorder Initial Treatment Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients were administered fluoxetine doses of 10 to 20 mg/day (see CLINICAL TRIALS). Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All patients — As with other drugs effective in the treatment of major depressive disorder, the full effect may be delayed until 4 weeks of treatment or longer. As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Daily Dosing Systematic evaluation of Prozac in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day (see CLINICAL TRIALS). Weekly Dosing Systematic evaluation of Prozac Weekly in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with Prozac 20 mg once daily. However, therapeutic equivalence of Prozac Weekly given on a once-weekly basis with Prozac 20 mg given daily for delaying time to relapse has not been established (see CLINICAL TRIALS). Weekly dosing with Prozac Weekly capsules is recommended to be initiated 7 days after the last daily dose of Prozac 20 mg (see Weekly dosing under CLINICAL PHARMACOLOGY). If satisfactory response is not maintained with Prozac Weekly, consider reestablishing a daily dosing regimen (see CLINICAL TRIALS). Switching Patients to a Tricyclic Antidepressant (TCA) Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS, Drug Interactions). Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping Prozac before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS). Obsessive Compulsive Disorder Initial Treatment Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo (see CLINICAL TRIALS). In 1 of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once-a-day (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. Pediatric (children and adolescents) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see CLINICAL TRIALS). In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. All patients — As with the use of Prozac in the treatment of major depressive disorder, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment While there are no systematic studies that answer the question of how long to continue Prozac, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of Prozac after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. Bulimia Nervosa Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo (see CLINICAL TRIALS). Only the 60-mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. As with the use of Prozac in the treatment of major depressive disorder and OCD, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment Systematic evaluation of continuing Prozac 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking Prozac 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment (see CLINICAL TRIALS). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Panic Disorder Initial Treatment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see CLINICAL TRIALS). Treatment should be initiated with a dose of 10 mg/day. After 1 week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic disorder. As with the use of Prozac in other indications, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly (see Geriatric Use under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS). Maintenance/Continuation Treatment While there are no systematic studies that answer the question of how long to continue Prozac, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Prozac and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Prozac during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Prozac in the third trimester. Discontinuation of Treatment with Prozac Symptoms associated with discontinuation of Prozac and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. HOW SUPPLIED The following products are manufactured by Eli Lilly and Company for Dista Products Company. Prozac® Pulvules®, USP, are available in: The 10-mg1, Pulvule is opaque green and green, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body: NDC 0777-3104-02 (PU31042) - Bottles of 100 The 20-mg1 Pulvule is an opaque green cap and off-white body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 NDC 0777-3105-30 (PU31052) - Bottles of 30 NDC 0777-3105-02 (PU31052) - Bottles of 100 NDC 0777-3105-07 (PU31052) - Bottles of 2000 The 40-mg1 Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body: NDC 0777-3107-30 (PU31072) - Bottles of 30 The following is manufactured by OSG Norwich Pharmaceuticals, Inc., North Norwich, NY, 13814, for Dista Products Company: Liquid, Oral Solution is available in: 20 mg1 per 5 mL with mint flavor: NDC 0777-5120-58 (MS-51203) - Bottles of 120 mL Prozac® Weekly™ Capsules are available in: The 90-mg1 capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body. NDC 0002-3004-75 (PU3004) - Blister package of 4 ______________________ 1 Fluoxetine base equivalent. 2 Protect from light. 3 Dispense in a tight, light-resistant container. Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F). ANIMAL TOXICOLOGY Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown. ___________________________________________________________________________ Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your health care provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child’s life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. Whenever an antidepressant is started or its dose is changed, pay close attention to your child. After starting an antidepressant, your child should generally see his or her health care provider • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your health care provider’s advice about how often to come back • More often if problems or questions arise (see Section 3) You should call your child’s health care provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child’s health care provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child’s teacher: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her health care provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your health care provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®). Your health care provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your health care provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your health care provider or pharmacist where to find more information. Prozac® is a registered trademark of Eli Lilly and Company. Zoloft® is a registered trademark of Pfizer Pharmaceuticals. Anafranil® is a registered trademark of Mallinckrodt Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 This Medication Guide has been approved by the US Food and Drug Administration for all antidepressants. Literature revised August 9, 2006 Eli Lilly and Company Indianapolis, IN 46285, USA www.lilly.com PV 5321 DPP PRINTED IN USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 PV 5413 AMP SYMBYAX® (olanzapine and fluoxetine HCl capsules) WARNING Suicidality in Children and Adolescents — Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of SYMBYAX or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SYMBYAX is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS, Pediatric Use.) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infections (e.g., pneumonia) in nature. SYMBYAX (olanzapine and fluoxetine HCl) is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS). DESCRIPTION SYMBYAX® (olanzapine and fluoxetine HCl capsules) combines 2 psychotropic agents, olanzapine (the active ingredient in Zyprexa®, and Zyprexa Zydis®) and fluoxetine hydrochloride (the active ingredient in Prozac®, Prozac Weekly™, and Sarafem®). Olanzapine belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl- 4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular weight of 312.44. Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI). The chemical designation is (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride. The molecular formula is C17H18F3NO•HCl, which corresponds to a molecular weight of 345.79. The chemical structures are: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 olanzapine fluoxetine hydrochloride Olanzapine is a yellow crystalline solid, which is practically insoluble in water. Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. SYMBYAX capsules are available for oral administration in the following strength combinations: 6 mg/25 mg 6 mg/50 mg 12 mg/25 mg 12 mg/50 mg olanzapine equivalent 6 6 12 12 fluoxetine base equivalent 25 50 25 50 Each capsule also contains pregelatinized starch, gelatin, dimethicone, titanium dioxide, sodium lauryl sulfate, edible black ink, red iron oxide, yellow iron oxide, and/or black iron oxide. CLINICAL PHARMACOLOGY Pharmacodynamics Although the exact mechanism of SYMBYAX is unknown, it has been proposed that the activation of 3 monoaminergic neural systems (serotonin, norepinephrine, and dopamine) is responsible for its enhanced antidepressant effect. This is supported by animal studies in which the olanzapine/fluoxetine combination has been shown to produce synergistic increases in norepinephrine and dopamine release in the prefrontal cortex compared with either component alone, as well as increases in serotonin. Olanzapine is a psychotropic agent with high affinity binding to the following receptors: serotonin 5HT2A/2C (Ki=4 and 11 nM, respectively), dopamine D1-4 (Ki=11 to 31 nM), muscarinic M1-5 (Ki=1.9 to 25 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine binds weakly to GABAA, BZD, and β-adrenergic receptors (Ki>10 µM). Fluoxetine is an inhibitor of the serotonin transporter and is a weak inhibitor of the norepinephrine and dopamine transporters. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of olanzapine. Olanzapine’s antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. The antagonism of histamine H1 receptors by olanzapine may explain the somnolence observed with this drug. The antagonism of α1-adrenergic receptors by olanzapine may explain the orthostatic hypotension . NHCH3 O CF 3 HCl N N H S CH3 N N CH3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 observed with this drug. Fluoxetine has relatively low affinity for muscarinic, α1-adrenergic, and histamine H1 receptors. Pharmacokinetics Fluoxetine (administered as a 60-mg single dose or 60 mg daily for 8 days) caused a small increase in the mean maximum concentration of olanzapine (16%) following a 5-mg dose, an increase in the mean area under the curve (17%) and a small decrease in mean apparent clearance of olanzapine (16%). In another study, a similar decrease in apparent clearance of olanzapine of 14% was observed following olanzapine doses of 6 or 12 mg with concomitant fluoxetine doses of 25 mg or more. The decrease in clearance reflects an increase in bioavailability. The terminal half-life is not affected, and therefore the time to reach steady state should not be altered. The overall steady-state plasma concentrations of olanzapine and fluoxetine when given as the combination in the therapeutic dose ranges were comparable with those typically attained with each of the monotherapies. The small change in olanzapine clearance, observed in both studies, likely reflects the inhibition of a minor metabolic pathway for olanzapine via CYP2D6 by fluoxetine, a potent CYP2D6 inhibitor, and was not deemed clinically significant. Therefore, the pharmacokinetics of the individual components is expected to reasonably characterize the overall pharmacokinetics of the combination. Absorption and Bioavailability SYMBYAX — Following a single oral 12-mg/50-mg dose of SYMBYAX, peak plasma concentrations of olanzapine and fluoxetine occur at approximately 4 and 6 hours, respectively. The effect of food on the absorption and bioavailability of SYMBYAX has not been evaluated. The bioavailability of olanzapine given as Zyprexa, and the bioavailability of fluoxetine given as Prozac were not affected by food. It is unlikely that there would be a significant food effect on the bioavailability of SYMBYAX. Olanzapine — Olanzapine is well absorbed and reaches peak concentration approximately 6 hours following an oral dose. Food does not affect the rate or extent of olanzapine absorption when olanzapine is given as Zyprexa. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Fluoxetine — Following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. Food does not appear to affect the systemic bioavailability of fluoxetine given as Prozac, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Distribution SYMBYAX — The in vitro binding to human plasma proteins of the olanzapine/fluoxetine combination is similar to the binding of the individual components. Olanzapine — Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α1-acid glycoprotein. Fluoxetine — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated (see PRECAUTIONS, Drugs tightly bound to plasma proteins). Metabolism and Elimination SYMBYAX — SYMBYAX therapy yielded steady-state concentrations of norfluoxetine similar to those seen with fluoxetine in the therapeutic dose range. Olanzapine — Olanzapine displays linear pharmacokinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 olanzapine once daily leads to steady-state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age (see Special Populations). Following a single oral dose of 14C-labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4´-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed. Direct glucuronidation and CYP450-mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYP1A2, CYP2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6-mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme. Fluoxetine — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Fluoxetine is extensively metabolized in the liver to its only identified active metabolite, norfluoxetine, via the CYP2D6 pathway. A number of unidentified metabolites exist. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical Issues Related to Metabolism and Elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect the clinical use of SYMBYAX. Variability in metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme CYP2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative nonsaturable pathways (non-CYP2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because the metabolism of fluoxetine, like that of a number of other compounds including TCAs and other selective serotonin antidepressants, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see PRECAUTIONS, Drug Interactions). Accumulation and slow elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because the metabolism of fluoxetine is not proportional to dose. However, norfluoxetine appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Special Populations Geriatric — Based on the individual pharmacokinetic profiles of olanzapine and fluoxetine, the pharmacokinetics of SYMBYAX may be altered in geriatric patients. Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity. In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly subjects (>65 years of age) than in non-elderly subjects (≤65 years of age). The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events was observed in those elderly patients. Renal Impairment — The pharmacokinetics of SYMBYAX has not been studied in patients with renal impairment. However, olanzapine and fluoxetine individual pharmacokinetics do not differ significantly in patients with renal impairment. SYMBYAX dosing adjustment based upon renal impairment is not routinely required. Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on olanzapine metabolite elimination has not been studied. In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. Hepatic Impairment — Based on the individual pharmacokinetic profiles of olanzapine and fluoxetine, the pharmacokinetics of SYMBYAX may be altered in patients with hepatic impairment. The lowest starting dose should be considered for patients with hepatic impairment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 (see PRECAUTIONS, Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION, Special Populations). Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (N=6) with clinically significant cirrhosis (Childs-Pugh Classification A and B) revealed little effect on the pharmacokinetics of olanzapine. As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. Gender — Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed. Smoking Status — Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely required. Race — No SYMBYAX pharmacokinetic study was conducted to investigate the effects of race. Results from an olanzapine cross-study comparison between data obtained in Japan and data obtained in the US suggest that exposure to olanzapine may be about 2-fold greater in the Japanese when equivalent doses are administered. Olanzapine clinical study safety and efficacy data, however, did not suggest clinically significant differences among Caucasian patients, patients of African descent, and a 3rd pooled category including Asian and Hispanic patients. Dosage modifications for race, therefore, are not routinely required. Combined Effects — The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance of olanzapine in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. SYMBYAX dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of the olanzapine component (see DOSAGE AND ADMINISTRATION, Special Populations). CLINICAL STUDIES The efficacy of SYMBYAX for the treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed, 8-week, randomized, double-blind, controlled studies of patients who met Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for Bipolar I Disorder, Depressed utilizing flexible dosing of SYMBYAX (6/25, 6/50, or 12/50 mg/day), olanzapine (5 to 20 mg/day), and placebo. These studies included patients (≥18 years of age) with or without psychotic symptoms and with or without a rapid cycling course. The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 to 60. The primary outcome measure of these studies was the change from baseline to endpoint in the MADRS total score. In both studies, SYMBYAX was statistically significantly superior to both olanzapine monotherapy and placebo in reduction of the MADRS total score. The results of the studies are summarized below (Table 1). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Table 1: MADRS Total Score Mean Change from Baseline to Endpoint Treatment Group Baseline Mean Change to Endpoint Mean1 SYMBYAX (N=40) 30 -16a Olanzapine (N=182) 32 -12 Study 1 Placebo (N=181) 31 -10 SYMBYAX (N=42) 32 -18a Olanzapine (N=169) 33 -14 Study 2 Placebo (N=174) 31 -9 1 Negative number denotes improvement from baseline. a Statistically significant compared to both olanzapine and placebo. INDICATIONS AND USAGE SYMBYAX is indicated for the treatment of depressive episodes associated with bipolar disorder. The efficacy of SYMBYAX was established in 2 identically designed, 8-week, randomized, double-blind clinical studies. Unlike with unipolar depression, there are no established guidelines for the length of time patients with bipolar disorder experiencing a major depressive episode should be treated with agents containing antidepressant drugs. The effectiveness of SYMBYAX for maintaining antidepressant response in this patient population beyond 8 weeks has not been established in controlled clinical studies. Physicians who elect to use SYMBYAX for extended periods should periodically reevaluate the benefits and long-term risks of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity — SYMBYAX is contraindicated in patients with a known hypersensitivity to the product or any component of the product. Monoamine Oxidase Inhibitors (MAOI) — There have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with an MAOI, and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, SYMBYAX should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination)] should be allowed after stopping SYMBYAX before starting an MAOI. Pimozide — Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Thioridazine — Thioridazine should not be administered with SYMBYAX or administered within a minimum of 5 weeks after discontinuation of SYMBYAX (see WARNINGS, Thioridazine). WARNINGS Clinical Worsening and Suicide Risk — Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with SYMBYAX, for a description of the risks of discontinuation of SYMBYAX). Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for SYMBYAX should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. It should be noted that SYMBYAX is not approved for use in treating any indications in the pediatric population. Screening Patients for Bipolar Disorder — A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that SYMBYAX is approved for use in treating bipolar depression. Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. SYMBYAX (olanzapine and fluoxetine HCl) is not approved for the treatment of patients with dementia-related psychosis (see BOX WARNING). In olanzapine placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively). Cerebrovascular Adverse Events (CVAE), Including Stroke, in Elderly Patients with Dementia-Related Psychosis — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Hyperglycemia and Diabetes Mellitus — Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including olanzapine alone, as well as olanzapine taken concomitantly with fluoxetine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Orthostatic Hypotension — SYMBYAX may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope, especially during the initial dose-titration period. In the bipolar depression studies, statistically significantly more orthostatic changes occurred with the SYMBYAX group compared to placebo and olanzapine groups. Orthostatic systolic blood pressure decrease of at least 30 mm Hg occurred in 7.3% (6/82), 1.4% (5/346), and 1.4% (5/352) of the SYMBYAX, olanzapine and placebo groups, respectively. Among the group of controlled clinical studies with SYMBYAX, an orthostatic systolic blood pressure decrease of ≥30 mm Hg occurred in 4% (21/512) of SYMBYAX-treated patients, 5% (10/204) of fluoxetine-treated patients, 2% (16/644) of olanzapine-treated patients, and 2% (8/445) of placebo-treated patients. In this group of studies, the incidence of syncope in SYMBYAX-treated patients was 0.4% (2/571) compared to placebo 0.2% (1/477). In a clinical pharmacology study of SYMBYAX, three healthy subjects were discontinued from the trial after experiencing severe, but self-limited, hypotension and bradycardia that occurred 2 to 9 hours following a single 12-mg/50-mg dose of SYMBYAX. Reactions consisting of this combination of hypotension and bradycardia (and also accompanied by sinus pause) have been observed in at least three other healthy subjects treated with various formulations of olanzapine (one oral, two intramuscular). In controlled clinical studies, the incidence of patients with a ≥20 bpm decrease in orthostatic pulse concomitantly with a ≥20 mm Hg decrease in orthostatic systolic blood pressure was 0.4% (2/549) in the SYMBYAX group, 0.2% (1/455) in the placebo group, 0.8% (5/659) in the olanzapine group, and 0% (0/241) in the fluoxetine group. SYMBYAX should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). Allergic Events and Rash — In SYMBYAX premarketing controlled clinical studies, the overall incidence of rash or allergic events in SYMBYAX-treated patients [4.6% (26/571)] was similar to that of placebo [5.2% (25/477)]. The majority of the cases of rash and/or urticaria were mild; however, three patients discontinued (one due to rash, which was moderate in severity, and two due to allergic events, one of which included face edema). In fluoxetine US clinical studies, 7% of 10,782 fluoxetine-treated patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical studies, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In fluoxetine premarketing clinical studies, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but 1 was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of fluoxetine, systemic events, possibly related to vasculitis, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. Anaphylactoid events, including bronchospasm, angioedema, and urticaria alone and in combination, have been reported. Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possible allergic phenomena for which an alternative etiology cannot be identified, SYMBYAX should be discontinued. Serotonin Syndrome — The development of a potentially life-threatening serotonin syndrome may occur with SYMBYAX treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of SYMBYAX with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors (MAOI) and PRECAUTIONS, Drug Interactions). If concomitant treatment of SYMBYAX with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions). The concomitant use of SYMBYAX with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions). Neuroleptic Malignant Syndrome (NMS) — A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If after recovering from NMS, a patient requires treatment with an antipsychotic, the patient should be carefully monitored, since recurrences of NMS have been reported. Tardive Dyskinesia — A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. The incidence of dyskinetic movement in SYMBYAX-treated patients was infrequent. The mean score on the Abnormal Involuntary Movement Scale (AIMS) across clinical studies involving SYMBYAX-treated patients decreased from baseline. Nonetheless, SYMBYAX should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on SYMBYAX, drug discontinuation should be considered. However, some patients may require treatment with SYMBYAX despite the presence of the syndrome. The need for continued treatment should be reassessed periodically. Thioridazine — In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25-mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs that inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS). Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS, Thioridazine). PRECAUTIONS General Concomitant Use of Olanzapine and Fluoxetine Products — SYMBYAX contains the same active ingredients that are in Zyprexa and Zyprexa Zydis (olanzapine) and in Prozac, Prozac Weekly, and Sarafem (fluoxetine HCl). Caution should be exercised when prescribing these medications concomitantly with SYMBYAX. Abnormal Bleeding — Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of SYMBYAX with NSAIDs, aspirin, or other drugs that affect coagulation. Mania/Hypomania — In the two controlled bipolar depression studies there was no statistically significant difference in the incidence of manic events (manic reaction or manic depressive reaction) between SYMBYAX- and placebo-treated patients. In one of the studies, the incidence of manic events was (7% [3/43]) in SYMBYAX-treated patients compared to (3% [5/184]) in placebo-treated patients. In the other study, the incidence of manic events was (2% [1/43]) in SYMBYAX-treated patients compared to (8% [15/193]) in placebo-treated patients. This limited controlled trial experience of SYMBYAX in the treatment of bipolar depression makes it difficult to interpret these findings until additional data is obtained. Because of this and the cyclical nature of bipolar disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with SYMBYAX. Body Temperature Regulation — Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic drugs. Appropriate care is advised when prescribing SYMBYAX for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration). Cognitive and Motor Impairment — Somnolence was a commonly reported adverse event associated with SYMBYAX treatment, occurring at an incidence of 22% in SYMBYAX patients compared with 11% in placebo patients. Somnolence led to discontinuation in 2% (10/571) of patients in the premarketing controlled clinical studies. As with any CNS-active drug, SYMBYAX has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that SYMBYAX therapy does not affect them adversely. Discontinuation of Treatment with SYMBYAX During marketing of fluoxetine, a component of SYMBYAX, and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION). Dysphagia — Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease. Olanzapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Half-Life — Because of the long elimination half-lives of fluoxetine and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination). Hyperprolactinemia — As with other drugs that antagonize dopamine D2 receptors, SYMBYAX elevates prolactin levels, and a modest elevation persists during administration; however, possibly associated clinical manifestations (e.g., galactorrhea and breast enlargement) were infrequently observed. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer of this type. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. As is common with compounds that increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats (see Carcinogenesis). However, neither clinical studies nor epidemiologic studies have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive. Hyponatremia — Hyponatremia has been observed in SYMBYAX premarketing clinical studies. In controlled trials, no SYMBYAX-treated patients had a treatment-emergent serum sodium below 130 mmol/L; however, a lowering of serum sodium below the reference range occurred at an incidence of 2% (10/500) of SYMBYAX patients compared with 0.5% (2/380) of placebo patients. In open label studies, 0.3% (5/1889) of these SYMBYAX-treated patients had a treatment-emergent serum sodium below 130 mmol/L. Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported with fluoxetine. The hyponatremia appeared to be reversible when fluoxetine was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted. In two 6-week controlled studies in patients ≥60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration was 129 mmol/L. The observed decreases were not clinically significant. Seizures — Seizures occurred in 0.2% (4/2066) of SYMBYAX-treated patients during open-label premarketing clinical studies. No seizures occurred in the premarketing controlled SYMBYAX studies. Seizures have also been reported with both olanzapine and fluoxetine monotherapy. Therefore, SYMBYAX should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of ≥65 years of age. Transaminase Elevations — As with olanzapine, asymptomatic elevations of hepatic transaminases [ALT (SGPT), AST (SGOT), and GGT] and alkaline phosphatase have been observed with SYMBYAX. In the SYMBYAX-controlled database, ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 6.3% (31/495) of patients exposed to SYMBYAX compared with 0.5% (2/384) of the placebo patients and 4.5% (25/560) of olanzapine-treated patients. The difference between SYMBYAX and placebo was statistically significant. None of these 31 SYMBYAX-treated patients experienced jaundice and three had transient elevations >200 IU/L. In olanzapine placebo-controlled studies, clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2% (6/243) of patients exposed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 to olanzapine compared with 0% (0/115) of the placebo patients. None of these patients experienced jaundice. In 2 of these patients, liver enzymes decreased toward normal despite continued treatment, and in 2 others, enzymes decreased upon discontinuation of olanzapine. In the remaining 2 patients, 1, seropositive for hepatitis C, had persistent enzyme elevations for 4 months after discontinuation, and the other had insufficient follow-up to determine if enzymes normalized. Within the larger olanzapine premarketing database of about 2400 patients with baseline SGPT ≤90 IU/L, the incidence of SGPT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued. Among all 2500 patients in olanzapine clinical studies, approximately 1% (23/2500) discontinued treatment due to transaminase increases. Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period. Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs. Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Laboratory Tests). Weight Gain — In clinical studies, the mean weight increase for SYMBYAX-treated patients was statistically significantly greater than placebo-treated (3.6 kg vs -0.3 kg) and fluoxetine-treated (3.6 kg vs -0.7 kg) patients, but was not statistically significantly different from olanzapine-treated patients (3.6 kg vs 3.0 kg). Fourteen percent of SYMBYAX-treated patients met criterion for having gained >10% of their baseline weight. This was statistically significantly greater than placebo-treated (<1%) and fluoxetine-treated patients (<1%) but was not statistically significantly different than olanzapine-treated patients (11%). Use in Patients with Concomitant Illness Clinical experience with SYMBYAX in patients with concomitant systemic illnesses is limited (see CLINICAL PHARMACOLOGY, Renal Impairment and Hepatic Impairment). The following precautions for the individual components may be applicable to SYMBYAX. Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical studies, SYMBYAX was associated with constipation, dry mouth, and tachycardia, all adverse events possibly related to cholinergic antagonism. Such adverse events were not often the basis for study discontinuations; SYMBYAX should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, a history of paralytic ileus, or related conditions. In five placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse events were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse events was significantly greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised (see BOX WARNING and WARNINGS). As with other CNS-active drugs, SYMBYAX should be used with caution in elderly patients with dementia. Olanzapine is not approved for the treatment of patients with dementia-related This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised (see BOX WARNING and WARNINGS). SYMBYAX has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the premarket testing. Caution is advised when using SYMBYAX in cardiac patients and in patients with diseases or conditions that could affect hemodynamic responses (see WARNINGS, Orthostatic Hypotension). In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower dose of the fluoxetine-component of SYMBYAX should be used in patients with cirrhosis. Caution is advised when using SYMBYAX in patients with diseases or conditions that could affect its metabolism (see CLINICAL PHARMACOLOGY, Hepatic Impairment and DOSING AND ADMINISTRATION, Special Populations). Olanzapine and fluoxetine individual pharmacokinetics do not differ significantly in patients with renal impairment. SYMBYAX dosing adjustment based upon renal impairment is not routinely required (see CLINICAL PHARMACOLOGY, Renal Impairment). Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with SYMBYAX and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for SYMBYAX. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking SYMBYAX. Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SYMBYAX and triptans, tramadol or other serotonergic agents. Abnormal Bleeding — Patients should be cautioned about the concomitant use of SYMBYAX and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Alcohol — Patients should be advised to avoid alcohol while taking SYMBYAX. Cognitive and Motor Impairment — As with any CNS-active drug, SYMBYAX has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 operating hazardous machinery, including automobiles, until they are reasonably certain that SYMBYAX therapy does not affect them adversely. Concomitant Medication — Patients should be advised to inform their physician if they are taking Prozac®, Prozac Weekly™, Sarafem®, fluoxetine, Zyprexa®, or Zyprexa Zydis®. Patients should also be advised to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions. Heat Exposure and Dehydration — Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Nursing — Patients, if taking SYMBYAX, should be advised not to breast-feed. Orthostatic Hypotension — Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol (see WARNINGS and Drug Interactions). Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during SYMBYAX therapy. Rash — Patients should be advised to notify their physician if they develop a rash or hives while taking SYMBYAX. Treatment Adherence — Patients should be advised to take SYMBYAX exactly as prescribed, and to continue taking SYMBYAX as prescribed even after their mood symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking SYMBYAX, without consulting their physician. Patient information is printed at the end of this insert. Physicians should discuss this information with their patients and instruct them to read the Medication Guide before starting therapy with SYMBYAX and each time their prescription is refilled. Laboratory Tests Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Transaminase Elevations). Drug Interactions The risks of using SYMBYAX in combination with other drugs have not been extensively evaluated in systematic studies. The drug-drug interactions of the individual components are applicable to SYMBYAX. As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. Caution is advised if the concomitant administration of SYMBYAX and other CNS-active drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination). Antihypertensive agents — Because of the potential for olanzapine to induce hypotension, SYMBYAX may enhance the effects of certain antihypertensive agents (see WARNINGS, Orthostatic Hypotension). Anti-Parkinsonian — The olanzapine component of SYMBYAX may antagonize the effects of levodopa and dopamine agonists. Benzodiazepines — Multiple doses of olanzapine did not influence the pharmacokinetics of diazepam and its active metabolite N-desmethyldiazepam. However, the coadministration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine. When concurrently administered with fluoxetine, the half-life of diazepam may be prolonged in some patients (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Biperiden — Multiple doses of olanzapine did not influence the pharmacokinetics of biperiden. Carbamazepine — Carbamazepine therapy (200 mg BID) causes an approximate 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance. Patients on stable doses of carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Clozapine — Elevation of blood levels of clozapine has been observed in patients receiving concomitant fluoxetine. Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment (see Seizures). Ethanol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The coadministration of ethanol with SYMBYAX may potentiate sedation and orthostatic hypotension. Fluvoxamine — Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine administration of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of the olanzapine component of SYMBYAX should be considered in patients receiving concomitant treatment with fluvoxamine. Haloperidol — Elevation of blood levels of haloperidol has been observed in patients receiving concomitant fluoxetine. Lithium — Multiple doses of olanzapine did not influence the pharmacokinetics of lithium. There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored in patients taking SYMBYAX concomitantly with lithium. Monoamine oxidase inhibitors — See CONTRAINDICATIONS. Phenytoin — Patients on stable doses of phenytoin have developed elevated plasma levels of phenytoin with clinical phenytoin toxicity following initiation of concomitant fluoxetine. Pimozide — Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine. Concomitant use of fluoxetine and pimozide is contraindicated (see CONTRAINDICATIONS). Serotonergic drugs — Based on the mechanism of action of SYMBYAX and the potential for serotonin syndrome, caution is advised when SYMBYAX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see WARNINGS, Serotonin Syndrome). The concomitant use of SYMBYAX with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites. Thioridazine — See CONTRAINDICATIONS and WARNINGS, Thioridazine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Tricyclic antidepressants (TCAs) — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine. In two fluoxetine studies, previously stable plasma levels of imipramine and desipramine have increased >2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for three weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when SYMBYAX is coadministered or has been recently discontinued (see Drugs metabolized by CYP2D6 and CLINICAL PHARMACOLOGY, Accumulation and slow elimination). Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of SYMBYAX with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Tryptophan — Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. Valproate — In vitro studies using human liver microsomes determined that olanzapine has little potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further, valproate has little effect on the metabolism of olanzapine in vitro. Thus, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely. Warfarin — Warfarin (20-mg single dose) did not affect olanzapine pharmacokinetics. Single doses of olanzapine did not affect the pharmacokinetics of warfarin. Altered anticoagulant effects, including increased bleeding, have been reported when fluoxetine is coadministered with warfarin (see PRECAUTIONS, Abnormal Bleeding). Patients receiving warfarin therapy should receive careful coagulation monitoring when SYMBYAX is initiated or stopped. Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.) — Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Thus, patients should be cautioned about the use of such drugs concurrently with SYMBYAX. Drugs metabolized by CYP2D6 — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP2D6. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by this enzyme. Approximately 7% of the normal population has a genetic variation that leads to reduced levels of activity of CYP2D6. Such individuals have been referred to as poor metabolizers of drugs such as debrisoquin, dextromethorphan, and TCAs. Many drugs, such as most antidepressants, including fluoxetine and other selective uptake inhibitors of serotonin, are metabolized by this isoenzyme; thus, both the pharmacokinetic properties and relative proportion of metabolites are altered in poor metabolizers. However, for fluoxetine and its metabolite, the sum of the plasma concentrations of the 4 enantiomers is comparable between poor and extensive metabolizers (see CLINICAL PHARMACOLOGY, Variability in metabolism). Fluoxetine, like other agents that are metabolized by CYP2D6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble poor metabolizers. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous five weeks. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for a decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (including but not limited to, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 flecainide, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated thioridazine plasma levels, thioridazine should not be administered with fluoxetine or within a minimum of five weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors (MAOI) and WARNINGS, Thioridazine). Drugs metabolized by CYP3A — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes. In an in vivo interaction study involving the coadministration of fluoxetine with single doses of terfenadine (a CYP3A substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A activity is not likely to be of clinical significance. Effect of olanzapine on drugs metabolized by other CYP enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, and CYP2C19. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes. The effect of other drugs on olanzapine — Fluoxetine, an inhibitor of CYP2D6, decreases olanzapine clearance a small amount (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance. Fluvoxamine, an inhibitor of CYP1A2, decreases olanzapine clearance (see Drug Interactions, Fluvoxamine). The effect of CYP1A2 inhibitors, such as fluvoxamine and some fluoroquinolone antibiotics, on SYMBYAX has not been evaluated. Although olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter olanzapine clearance. Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs. Drugs tightly bound to plasma proteins — The in vitro binding of SYMBYAX to human plasma proteins is similar to the individual components. The interaction between SYMBYAX and other highly protein-bound drugs has not been fully evaluated. Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs (see CLINICAL PHARMACOLOGY, Distribution and PRECAUTIONS, Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity, mutagenicity, or fertility studies were conducted with SYMBYAX. The following data are based on findings in studies performed with the individual components. Carcinogenesis Olanzapine — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, and 30/20 mg/kg/day [equivalent to 0.8 to 5 times the maximum recommended human daily dose (MRHD) on a mg/m2 basis] and 0.25, 2, and 8 mg/kg/day (equivalent to 0.06 to 2 times the MRHD on a mg/m2 basis). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, and 4 mg/kg/day (males) and 0.25, 1, 4, and 8 mg/kg/day (females) (equivalent to 0.1 to 2 and 0.1 to 4 times the MRHD on a mg/m2 basis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in one mouse study in females dosed at 8 mg/kg/day (2 times the MRHD on a mg/m2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 basis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2 to 5 times the MRHD on a mg/m2 basis); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the MRHD on a mg/m2 basis, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the finding of prolactin-mediated endocrine tumors in rodents is unknown (see PRECAUTIONS, Hyperprolactinemia). Fluoxetine — The dietary administration of fluoxetine to rats and mice for two years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times, respectively, the MRHD on a mg/m2 basis), produced no evidence of carcinogenicity. Mutagenesis Olanzapine — No evidence of mutagenic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. Fluoxetine — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of Fertility SYMBYAX — Fertility studies were not conducted with SYMBYAX. However, in a repeat-dose rat toxicology study of three months duration, ovary weight was decreased in females treated with the low-dose [2 and 4 mg/kg/day (1 and 0.5 times the MRHD on a mg/m2 basis), respectively] and high-dose [4 and 8 mg/kg/day (2 and 1 times the MRHD on a mg/m2 basis), respectively] combinations of olanzapine and fluoxetine. Decreased ovary weight, and corpora luteal depletion and uterine atrophy were observed to a greater extent in the females receiving the high-dose combination than in females receiving either olanzapine or fluoxetine alone. In a 3-month repeat-dose dog toxicology study, reduced epididymal sperm and reduced testicular and prostate weights were observed with the high-dose combination of olanzapine and fluoxetine [5 and 5 mg/kg/day (9 and 2 times the MRHD on a mg/m2 basis), respectively] and with olanzapine alone (5 mg/kg/day or 9 times the MRHD on a mg/m2 basis). Olanzapine — In a fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the MRHD on a mg/m2 basis, respectively). Discontinuance of olanzapine treatment reversed the effects on male-mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the MRHD on a mg/m2 basis). Diestrous was prolonged and estrous was delayed at 1.1 mg/kg/day (0.6 times the MRHD on a mg/m2 basis); therefore, olanzapine may produce a delay in ovulation. Fluoxetine — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Pregnancy — Pregnancy Category C SYMBYAX Embryo fetal development studies were conducted in rats and rabbits with olanzapine and fluoxetine in low-dose and high-dose combinations. In rats, the doses were: 2 and 4 mg/kg/day (low-dose) [1 and 0.5 times the MRHD on a mg/m2 basis, respectively], and 4 and 8 mg/kg/day (high-dose) [2 and 1 times the MRHD on a mg/m2 basis, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low-dose) [4 and 1 times the MRHD on a mg/m2 basis, respectively], and 8 and 8 mg/kg/day (high-dose) [9 and 2 times the MRHD on a mg/m2 basis, respectively]. In these studies, olanzapine and fluoxetine were also administered alone at the high-doses (4 and 8 mg/kg/day, respectively, in the rat; 8 and 8 mg/kg/day, respectively, in the rabbit). In the rabbit, there was no evidence of teratogenicity; however, the high-dose combination produced decreases in fetal weight and retarded skeletal ossification in conjunction with maternal toxicity. Similarly, in the rat there was no evidence of teratogenicity; however, a decrease in fetal weight was observed with the high-dose combination. In a pre- and postnatal study conducted in rats, olanzapine and fluoxetine were administered during pregnancy and throughout lactation in combination (low-dose: 2 and 4 mg/kg/day [1 and 0.5 times the MRHD on a mg/m2 basis], respectively, high-dose: 4 and 8 mg/kg/day [2 and 1 times the MRHD on a mg/m2 basis], respectively, and alone: 4 and 8 mg/kg/day [2 and 1 times the MRHD on a mg/m2 basis], respectively). Administration of the high-dose combination resulted in a marked elevation in offspring mortality and growth retardation in comparison to the same doses of olanzapine and fluoxetine administered alone. These effects were not observed with the low-dose combination; however, there were a few cases of testicular degeneration and atrophy, depletion of epididymal sperm and infertility in the male progeny. The effects of the high-dose combination on postnatal endpoints could not be assessed due to high progeny mortality. There are no adequate and well-controlled studies with SYMBYAX in pregnant women. SYMBYAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Olanzapine In reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the MRHD on a mg/m2 basis, respectively), no evidence of teratogenicity was observed. In a rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the MRHD on a mg/m2 basis). Gestation was prolonged at 10 mg/kg/day (5 times the MRHD on a mg/m2 basis). In a rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the MRHD on a mg/m2 basis). Placental transfer of olanzapine occurs in rat pups. There are no adequate and well-controlled clinical studies with olanzapine in pregnant women. Seven pregnancies were observed during premarketing clinical studies with olanzapine, including two resulting in normal births, one resulting in neonatal death due to a cardiovascular defect, three therapeutic abortions, and one spontaneous abortion. Fluoxetine In embryo fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times the MRHD on a mg/m2 basis, respectively) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Nonteratogenic Effects — Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). When treating a pregnant woman with fluoxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery SYMBYAX The effect of SYMBYAX on labor and delivery in humans is unknown. Parturition in rats was not affected by SYMBYAX. SYMBYAX should be used during labor and delivery only if the potential benefit justifies the potential risk. Olanzapine Parturition in rats was not affected by olanzapine. The effect of olanzapine on labor and delivery in humans is unknown. Fluoxetine The effect of fluoxetine on labor and delivery in humans is unknown. Fluoxetine crosses the placenta; therefore, there is a possibility that fluoxetine may have adverse effects on the newborn. Nursing Mothers SYMBYAX There are no adequate and well-controlled studies with SYMBYAX in nursing mothers or infants. No studies have been conducted to examine the excretion of olanzapine or fluoxetine in breast milk following SYMBYAX treatment. It is recommended that women not breast-feed when receiving SYMBYAX. Olanzapine Olanzapine was excreted in milk of treated rats during lactation. Fluoxetine Fluoxetine is excreted in human breast milk. In one breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the 2nd day of feeding. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 use of SYMBYAX in a child or adolescent must balance the potential risks with the clinical need. Fluoxetine Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain. Geriatric Use SYMBYAX Clinical studies of SYMBYAX did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Olanzapine Of the 2500 patients in premarketing clinical studies with olanzapine, 11% (263 patients) were ≥65 years of age. In patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared with younger patients. Studies in patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared with younger patients with schizophrenia. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised (see BOX WARNING, WARNINGS, PRECAUTIONS, Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION, Special Populations). As with other CNS-active drugs, olanzapine should be used with caution in elderly patients with dementia. Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient. Fluoxetine US fluoxetine clinical studies (10,782 patients) included 687 patients ≥65 years of age and 93 patients ≥75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other SSRIs, fluoxetine has been associated with cases of clinically significant hyponatremia in elderly patients. ADVERSE REACTIONS The information below is derived from a premarketing clinical study database for SYMBYAX consisting of 2066 patients with various diagnoses with approximately 1061 patient-years of exposure. The conditions and duration of treatment with SYMBYAX varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or long-term exposure. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The data in the tables represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is possible that events reported during therapy were not necessarily related to drug exposure. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing clinician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Incidence in Controlled Clinical Studies The following findings are based on the short-term, controlled premarketing studies in various diagnoses including bipolar depression. Adverse events associated with discontinuation of treatment — Overall, 10% of the patients in the SYMBYAX group discontinued due to adverse events compared with 4.6% for placebo. Table 2 enumerates the adverse events leading to discontinuation associated with the use of SYMBYAX (incidence of at least 1% for SYMBYAX and greater than that for placebo). The bipolar depression column shows the incidence of adverse events with SYMBYAX in the bipolar depression studies and the “SYMBYAX-Controlled” column shows the incidence in the controlled SYMBYAX studies; the placebo column shows the incidence in the pooled controlled studies that included a placebo arm. Table 2: Adverse Events Associated with Discontinuation* Percentage of Patients Reporting Event SYMBYAX Placebo Adverse Event Bipolar Depression (N=86) SYMBYAX-Controlled (N=571) (N=477) Asthenia 0 1 0 Somnolence 0 2 0 Weight gain 0 2 0 Chest pain 1 0 0 * Table includes events associated with discontinuation of at least 1% and greater than placebo Commonly observed adverse events in controlled clinical studies — The most commonly observed adverse events associated with the use of SYMBYAX (incidence of ≥5% and at least twice that for placebo in the SYMBYAX-controlled database) were: asthenia, edema, increased appetite, peripheral edema, pharyngitis, somnolence, thinking abnormal, tremor, and weight gain. Adverse events occurring at an incidence of 2% or more in controlled clinical studies — Table 3 enumerates the treatment-emergent adverse events associated with the use of SYMBYAX (incidence of at least 2% for SYMBYAX and twice or more that for placebo). Table 3: Treatment-Emergent Adverse Events: Incidence in Controlled Clinical Studies Percentage of Patients Reporting Event SYMBYAX Placebo Body System/ Adverse Event1 Bipolar Depression (N=86) SYMBYAX-Controlled (N=571) (N=477) Body as a Whole Asthenia 13 15 3 Accidental injury 5 3 2 Fever 4 3 1 Cardiovascular System Hypertension 2 2 1 Tachycardia 2 2 0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 Digestive System Diarrhea 19 8 7 Dry mouth 16 11 6 Increased appetite 13 16 4 Tooth disorder 1 2 1 Metabolic and Nutritional Disorders Weight gain 17 21 3 Peripheral edema 4 8 1 Edema 0 5 0 Musculoskeletal System Joint disorder 1 2 1 Twitching 6 2 1 Arthralgia 5 3 1 Nervous System Somnolence 21 22 11 Tremor 9 8 3 Thinking abnormal 6 6 3 Libido decreased 4 2 1 Hyperkinesia 2 1 1 Personality disorder 2 1 1 Sleep disorder 2 1 1 Amnesia 1 3 0 Respiratory System Pharyngitis 4 6 3 Dyspnea 1 2 1 Special Senses Amblyopia 5 4 2 Ear pain 2 1 1 Otitis media 2 0 0 Speech disorder 0 2 0 Urogenital System Abnormal ejaculation2 7 2 1 Impotence2 4 2 1 Anorgasmia 3 1 0 1 Included are events reported by at least 2% of patients taking SYMBYAX except the following events, which had an incidence on placebo ≥ SYMBYAX: abdominal pain, abnormal dreams, agitation, akathisia, anorexia, anxiety, apathy, back pain, chest pain, constipation, cough increased, depression, dizziness, dysmenorrhea (adjusted for gender), dyspepsia, flatulence, flu syndrome, headache, hypertonia, insomnia, manic reaction, myalgia, nausea, nervousness, pain, palpitation, paresthesia, rash, rhinitis, sinusitis, sweating, vomiting. 2 Adjusted for gender. Additional Findings Observed in Clinical Studies The following findings are based on clinical studies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 Effect on cardiac repolarization — The mean increase in QTc interval for SYMBYAX-treated patients (4.9 msec) in clinical studies was significantly greater than that for placebo-treated (-0.9 msec) and olanzapine-treated (0.6 msec) patients, but was not significantly different from fluoxetine-treated (3.7 msec) patients. There were no differences between patients treated with SYMBYAX, placebo, olanzapine, or fluoxetine in the incidence of QTc outliers (>500 msec). Laboratory changes — In SYMBYAX clinical studies, SYMBYAX was associated with asymptomatic mean increases in alkaline phosphatase, cholesterol, GGT, and uric acid compared with placebo (see PRECAUTIONS, Transaminase Elevations). SYMBYAX was associated with a slight decrease in hemoglobin that was statistically significantly greater than that seen with placebo, olanzapine, and fluoxetine. An elevation in serum prolactin was observed with SYMBYAX. This elevation was not statistically different than that seen with olanzapine (see PRECAUTIONS, Hyperprolactinemia). In olanzapine clinical studies among olanzapine-treated patients with random triglyceride levels of <150 mg/dL at baseline (N=659), 0.5% of patients experienced triglyceride levels of ≥500 mg/dL anytime during the trials. In these same trials, olanzapine-treated patients (N=1185) had a mean increase of 20 mg/dL in triglycerides from a mean baseline value of 175 mg/dL. In olanzapine placebo-controlled trials, olanzapine-treated patients with random cholesterol levels of <200 mg/dL at baseline (N=1034) experienced cholesterol levels of ≥240 mg/dL anytime during the trials more often than placebo-treated patients (N=602) (3.6% vs 2.2%, respectively). In these same trials, olanzapine-treated patients (N=2528) had a mean increase of 0.4 mg/dL in cholesterol from a mean baseline value of 203 mg/dL, which was significantly different compared to placebo-treated patients (N=1415) with a mean decrease of 4.6 mg/dL from a mean baseline value of 203 mg/dL. Sexual dysfunction — In the pool of controlled SYMBYAX studies, there were higher rates of the treatment–emergent adverse events decreased libido, anorgasmia, impotence and abnormal ejaculation in the SYMBYAX group than in the placebo group. One case of decreased libido led to discontinuation in the SYMBYAX group. In the controlled studies that contained a fluoxetine arm, the rates of decreased libido and abnormal ejaculation in the SYMBYAX group were less than the rates in the fluoxetine group. None of the differences were statistically significant. Sexual dysfunction, including priapism, has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Vital signs — Tachycardia, bradycardia, and orthostatic hypotension have occurred in SYMBYAX-treated patients (see WARNINGS, Orthostatic Hypotension). The mean pulse of SYMBYAX-treated patients was reduced by 1.6 beats/min. Other Events Observed in Clinical Studies Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking SYMBYAX in clinical studies except (1) those listed in the body or footnotes of Tables 2 and 3 above or elsewhere in labeling, (2) those for which the COSTART terms were uninformative or misleading, (3) those events for which a causal relationship to SYMBYAX use was considered remote, and (4) events occurring in only 1 patient treated with SYMBYAX and which did not have a substantial probability of being acutely life-threatening. Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on 1 or more occasions in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1000 patients, and rare events are those occurring in <1/1000 patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 Body as a Whole — Frequent: chills, infection, neck pain, neck rigidity, photosensitivity reaction; Infrequent: cellulitis, cyst, hernia, intentional injury, intentional overdose, malaise, moniliasis, overdose, pelvic pain, suicide attempt; Rare: death, tolerance decreased. Cardiovascular System — Frequent: migraine, vasodilatation; Infrequent: arrhythmia, bradycardia, cerebral ischemia, electrocardiogram abnormal, hypotension, QT-interval prolonged; Rare: angina pectoris, atrial arrhythmia, atrial fibrillation, bundle branch block, congestive heart failure, myocardial infarct, peripheral vascular disorder, T-wave inverted. Digestive System — Frequent: increased salivation, thirst; Infrequent: cholelithiasis, colitis, eructation, esophagitis, gastritis, gastroenteritis, gingivitis, hepatomegaly, nausea and vomiting, peptic ulcer, periodontal abscess, stomatitis, tooth caries; Rare: aphthous stomatitis, fecal incontinence, gastrointestinal hemorrhage, gum hemorrhage, intestinal obstruction, liver fatty deposit, pancreatitis. Endocrine System — Infrequent: hypothyroidism. Hemic and Lymphatic System — Frequent: ecchymosis; Infrequent: anemia, leukocytosis, lymphadenopathy; Rare: coagulation disorder, leukopenia, purpura, thrombocythemia. Metabolic and Nutritional — Frequent: generalized edema, weight loss; Infrequent: alcohol intolerance, dehydration, glycosuria, hyperlipemia, hypoglycemia, hypokalemia, obesity; Rare: acidosis, bilirubinemia, creatinine increased, gout, hyperkalemia, hypoglycemic reaction. Musculoskeletal System — Infrequent: arthritis, bone disorder, generalized spasm, leg cramps, tendinous contracture, tenosynovitis; Rare: arthrosis, bursitis, myasthenia, myopathy, osteoporosis, rheumatoid arthritis. Nervous System — Infrequent: abnormal gait, ataxia, buccoglossal syndrome, cogwheel rigidity, coma, confusion, depersonalization, dysarthria, emotional lability, euphoria, extrapyramidal syndrome, hostility, hypesthesia, hypokinesia, incoordination, movement disorder, myoclonus, neuralgia, neurosis, vertigo; Rare: acute brain syndrome, aphasia, dystonia, libido increased, subarachnoid hemorrhage, withdrawal syndrome. Respiratory System — Frequent: bronchitis, lung disorder; Infrequent: apnea, asthma, epistaxis, hiccup, hyperventilation, laryngitis, pneumonia, voice alteration, yawn; Rare: emphysema, hemoptysis, laryngismus. Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, pruritis, psoriasis, skin discoloration, vesiculobullous rash; Rare: exfoliative dermatitis, maculopapular rash, seborrhea, skin ulcer. Special Senses — Frequent: abnormal vision, taste perversion, tinnitus; Infrequent: abnormality of accommodation, conjunctivitis, deafness, diplopia, dry eyes, eye pain, miosis; Rare: eye hemorrhage. Urogenital System — Frequent: breast pain, menorrhagia1, urinary frequency, urinary incontinence, urinary tract infection; Infrequent: amenorrhea1, breast enlargement, breast neoplasm, cystitis, dysuria, female lactation1, fibrocystic breast1, hematuria, hypomenorrhea1, leukorrhea1, menopause1, metrorrhagia1, oliguria, ovarian disorder1, polyuria, urinary retention, urinary urgency, urination impaired, vaginal hemorrhage1, vaginal moniliasis1, vaginitis1; Rare: breast carcinoma, breast engorgement, endometrial disorder1, gynecomastia1, kidney calculus, uterine fibroids enlarged1. 1 Adjusted for gender. Other Events Observed with Olanzapine or Fluoxetine Monotherapy The following adverse events were not observed in SYMBYAX-treated patients during premarketing clinical studies but have been reported with olanzapine or fluoxetine monotherapy: aplastic anemia, cholestatic jaundice, diabetic coma, dyskinesia, eosinophilic pneumonia, erythema multiforme, hepatitis, idiosyncratic hepatitis, jaundice, priapism, pulmonary embolism, rhabdomyolysis, serotonin syndrome, serum sickness-like reaction, sudden unexpected death, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 suicidal ideation, vasculitis, venous thromboembolic events (including pulmonary embolism and deep venous thrombosis), violent behaviors. Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been rarely reported. DRUG ABUSE AND DEPENDENCE Controlled Substance Class — SYMBYAX is not a controlled substance. Physical and Psychological Dependence — SYMBYAX, as with fluoxetine and olanzapine, has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical studies did not reveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of SYMBYAX (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). In studies in rats and rhesus monkeys designed to assess abuse and dependence potential, olanzapine alone was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence at oral doses up to 15 (rat) and 8 (monkey) times the MRHD (20 mg) on a mg/m2 basis. OVERDOSAGE SYMBYAX During premarketing clinical studies of the olanzapine/fluoxetine combination, overdose of both fluoxetine and olanzapine were reported in five study subjects. Four of the five subjects experienced loss of consciousness (3) or coma (1). No fatalities occurred. Since the market introduction of olanzapine in October 1996, adverse event cases involving combination use of fluoxetine and olanzapine have been reported to Eli Lilly and Company. An overdose of combination therapy is defined as confirmed or suspected ingestion of a dose of olanzapine 20 mg or greater in combination with a dose of fluoxetine 80 mg or greater. As of 1 February 2002, 12 cases of combination therapy overdose were reported, most of which involved additional substances. Adverse events associated with these reports included somnolence; impaired consciousness (coma, lethargy); impaired neurologic function (ataxia, confusion, convulsions, dysarthria); arrhythmias; and fatality. Fatalities have been confounded by exposure to additional substances including alcohol, thioridazine, oxycodone, and propoxyphene. Olanzapine In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious events: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia as well as a patient that experienced sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg; however, in another case, a patient was reported to survive an acute olanzapine ingestion of 1500 mg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 Fluoxetine Worldwide exposure to fluoxetine is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdose, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdose were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the 6 fatalities was a 9-year-old boy who had a history of OCD, Tourette’s Syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams, which was non-lethal. Other important adverse events reported with fluoxetine overdose (single or multiple drugs) included coma, delirium, ECG abnormalities (such as QT-interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope. Management of Overdose — In managing overdose, the possibility of multiple drug involvement should be considered. In case of acute overdose, establish and maintain an airway and ensure adequate ventilation, which may include intubation. Induction of emesis is not recommended as the possibility of obtundation, seizures, or dystonic reactions of the head and neck following overdose may create a risk for aspiration. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. A specific precaution involves patients who are taking or have recently taken SYMBYAX and may have ingested excessive quantities of a TCA (tricyclic antidepressant). In such cases, accumulation of the parent TCA and/or an active metabolite may increase the possibility of serious sequelae and extend the time needed for close medical observation. Due to the large volume of distribution of olanzapine and fluoxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidote for either fluoxetine or olanzapine overdose is known. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. Do not use epinephrine, dopamine, or other sympathomimetics with β-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 DOSAGE AND ADMINISTRATION SYMBYAX should be administered once daily in the evening, generally beginning with the 6-mg/25-mg capsule. While food has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the absorption of SYMBYAX has not been studied. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Antidepressant efficacy was demonstrated with SYMBYAX in a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg (see CLINICAL STUDIES). The safety of doses above 18 mg/75 mg has not been evaluated in clinical studies. Special Populations The starting dose of SYMBYAX 6 mg/25 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of SYMBYAX (female gender, geriatric age, nonsmoking status). When indicated, dose escalation should be performed with caution in these patients. SYMBYAX has not been systematically studied in patients over 65 years of age or in patients <18 years of age (see WARNINGS, Orthostatic Hypotension, PRECAUTIONS, Pediatric Use, and Geriatric Use, and CLINICAL PHARMACOLOGY, Pharmacokinetics). Treatment of Pregnant Women During the Third Trimester Neonates exposed to fluoxetine, a component of SYMBYAX, and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with fluoxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering fluoxetine in the third trimester. Discontinuation of Treatment with SYMBYAX Symptoms associated with discontinuation of fluoxetine, a component of SYMBYAX, and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. HOW SUPPLIED SYMBYAX capsules are supplied in 6/25-, 6/50-, 12/25-, and 12/50-mg (mg equivalent olanzapine/mg equivalent fluoxetinea) strengths. SYMBYAX CAPSULE STRENGTH 6 mg/25 mg 6 mg/50 mg 12 mg/25 mg 12 mg/50 mg Mustard Yellow Mustard Yellow Red & Light Red & Light Color & Light Yellow & Light Grey Yellow Grey Capsule No. PU3231 PU3233 PU3232 PU3234 Lilly 3231 Lilly 3233 Lilly 3232 Lilly 3234 Identification 6/25 6/50 12/25 12/50 NDC Codes Bottles 30 0002-3231-30 0002-3233-30 0002-3232-30 0002-3234-30 Bottles 100 0002-3231-02 0002-3233-02 0002-3232-02 0002-3234-02 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 Bottles 1000 0002-3231-04 0002-3233-04 0002-3232-04 0002-3234-04 Blisters IDb100 0002-3231-33 0002-3233-33 0002-3232-33 0002-3234-33 a Fluoxetine base equivalent. b IDENTI-DOSE®, Unit Dose Medication, Lilly. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep tightly closed and protect from moisture. ____________________________________________________________________________ Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your health care provider before your child takes an antidepressant. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child’s life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. Whenever an antidepressant is started or its dose is changed, pay close attention to your child. After starting an antidepressant, your child should generally see his or her health care provider • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your health care provider’s advice about how often to come back • More often if problems or questions arise (see Section 3) You should call your child’s health care provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child’s health care provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child’s teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her health care provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 the risks of not treating it. You and your child should discuss all treatment choices with your health care provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®). Your health care provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your health care provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your health care provider or pharmacist where to find more information. Prozac® is a registered trademark of Eli Lilly and Company. Zoloft® is a registered trademark of Pfizer Pharmaceuticals. Anafranil® is a registered trademark of Mallinckrodt Inc. This Medication Guide has been approved by the US Food and Drug Administration for all antidepressants. Rx only Literature revised August 9, 2006 Eli Lilly and Company Indianapolis, IN 46285 www.SYMBYAX.com PV 5413 AMP PRINTED IN USA Copyright © 2003, 2006, Eli Lilly and Company. All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 PV 3607 AMP CYMBALTA® (duloxetine hydrochloride) Delayed-release Capsules WARNING Suicidality in Children and Adolescents — Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS, Pediatric Use.) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. DESCRIPTION Cymbalta® (duloxetine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1- naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C18H19NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is: Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water. Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 CLINICAL PHARMACOLOGY Pharmacodynamics Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine in humans are unknown, the antidepressant and pain inhibitory actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Pharmacokinetics Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2. Absorption and Distribution — Orally administered duloxetine hydrochloride is well absorbed. There is a median 2-hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3-hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose. The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment. Metabolism and Elimination — Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Special Populations Gender — Duloxetine’s half-life is similar in men and women. Dosage adjustment based on gender is not necessary. Age — The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary (see DOSAGE AND ADMINISTRATION). Smoking Status — Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers. Race — No specific pharmacokinetic study was conducted to investigate the effects of race. Renal Insufficiency — Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60-mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. For this reason, Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or severe renal impairment (estimated creatinine clearance [CrCl] <30 mL/min) (see DOSAGE AND ADMINISTRATION). Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance. Hepatic Insufficiency — Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. After a single 20-mg dose of Cymbalta, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer (see PRECAUTIONS). It is recommended that duloxetine not be administered to patients with any hepatic insufficiency (see DOSAGE AND ADMINISTRATION). Nursing Mothers — The disposition of duloxetine was studied in 6 lactating women who were at least 12-weeks postpartum. Duloxetine 40 mg BID was given for 3.5 days. Like many other drugs, duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 µg/day while on 40 mg BID dosing. Lactation did not influence duloxetine pharmacokinetics. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics (see DOSAGE AND ADMINISTRATION). Drug-Drug Interactions (also see PRECAUTIONS, Drug Interactions) Potential for Other Drugs to Affect Duloxetine Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Inhibitors of CYP1A2 — When duloxetine was co-administered with fluvoxamine, a potent CYP1A2 inhibitor, to male subjects (n=14) the AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Inhibitors of CYP2D6 — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations of duloxetine (see PRECAUTIONS, Drug Interactions). Studies with Benzodiazepines Lorazepam — Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration. Temazepam — Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. Potential for Duloxetine to Affect Other Drugs Drugs Metabolized by CYP1A2 — In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Although duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg BID). Duloxetine is thus unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates. Drugs Metabolized by CYP2D6 — Duloxetine is a moderate inhibitor of CYP2D6 and increases the AUC and Cmax of drugs metabolized by CYP2D6 (see PRECAUTIONS). Therefore, co-administration of Cymbalta with other drugs that are extensively metabolized by this isozyme and that have a narrow therapeutic index should be approached with caution (see PRECAUTIONS, Drug Interactions). Drugs Metabolized by CYP2C9 — Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated, although clinical studies have not been performed. Drugs Metabolized by CYP3A — Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed. Drugs Metabolized by CYP2C19 — Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed. Studies with Benzodiazepines Lorazepam — Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of lorazepam were not affected by co-administration. Temazepam — Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of temazepam were not affected by co-administration. Drugs Highly Bound to Plasma Protein — Because duloxetine is highly bound to plasma protein, administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. CLINICAL STUDIES Major Depressive Disorder The efficacy of Cymbalta as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 DSM-IV criteria for major depression. In 2 studies, patients were randomized to Cymbalta 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to Cymbalta 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to Cymbalta 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer any additional benefit. In all 4 studies, Cymbalta demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score. Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. Diabetic Peripheral Neuropathic Pain The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathy for at least 6 months. Study 1 and 2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to Cymbalta. Patients recorded their pain daily in a diary. Both studies compared Cymbalta 60 mg once daily or 60 mg twice daily with placebo. Study 1 additionally compared Cymbalta 20 mg with placebo. A total of 457 patients (342 Cymbalta, 115 placebo) were enrolled in Study 1 and a total of 334 patients (226 Cymbalta, 108 placebo) were enrolled in Study 2. Treatment with Cymbalta 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 1 and 2 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Figure 1: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - Study 1 Figure 2: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - Study 2 INDICATIONS AND USAGE Major Depressive Disorder Cymbalta is indicated for the treatment of major depressive disorder (MDD). The efficacy of Cymbalta has been established in 8- and 9-week placebo-controlled trials of outpatients who met DSM-IV diagnostic criteria for major depressive disorder (see CLINICAL STUDIES). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation. The effectiveness of Cymbalta in hospitalized patients with major depressive disorder has not been studied. The effectiveness of Cymbalta in long-term use for major depressive disorder, that is, for more than 9 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use Cymbalta for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient. Diabetic Peripheral Neuropathic Pain Cymbalta is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy (see CLINICAL STUDIES). CONTRAINDICATIONS Hypersensitivity Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients. Monoamine Oxidase Inhibitors Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). Uncontrolled Narrow-Angle Glaucoma In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma. WARNINGS Clinical Worsening and Suicide Risk — Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuing Cymbalta, for a description of the risks of discontinuation of Cymbalta). Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder — A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Cymbalta is not approved for use in treating bipolar depression. Monoamine Oxidase Inhibitors (MAOI) — In patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of Cymbalta and MAOIs have not been evaluated in humans or animals. Therefore, because Cymbalta is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that Cymbalta not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Cymbalta, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI. Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome may occur with Cymbalta treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Cymbalta with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Interaction with Monoamine Oxidase Inhibitors) If concomitant treatment of Cymbalta with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions). The concomitant use of Cymbalta with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions). PRECAUTIONS General Hepatotoxicity — Cymbalta increases the risk of elevation of serum transaminase levels. Liver transaminase elevations resulted in the discontinuation of 0.4% (31/8454) of Cymbalta-treated patients. In these patients, the median time to detection of the transaminase elevation was about two months. In controlled trials in MDD, elevations of alanine transaminase (ALT) to >3 times the upper limit of normal occurred in 0.9% (8/930) of Cymbalta-treated patients and in 0.3% (2/652) of placebo-treated patients. In controlled trials in DPN, elevations of ALT to >3 times the upper limit of normal occurred in 1.68% (8/477) of Cymbalta-treated patients and in 0% (0/187) of placebo-treated patients. In the full cohort of placebo-controlled trials in any indication, 1% (39/3732) of Cymbalta-treated patients had a >3 times the upper limit of normal elevation of ALT compared to 0.2% (6/2568) of placebo-treated patients. In placebo-controlled studies using a fixed-dose design, there was evidence of a dose-response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 respectively. Postmarketing reports have described cases of hepatitis with abdominal pain, hepatomegaly and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. The combination of transaminase elevations and elevated bilirubin, without evidence of obstruction, is generally recognized as an important predictor of severe liver injury. In clinical trials, three Cymbalta patients had elevations of transaminases and bilirubin, but also had elevation of alkaline phosphatase, suggesting an obstructive process; in these patients, there was evidence of heavy alcohol use and this may have contributed to the abnormalities seen. Two placebo-treated patients also had transaminase elevations with elevated bilirubin. Postmarketing reports indicate that elevated transaminases, bilirubin and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. Effect on Blood Pressure — In MDD clinical trials, Cymbalta treatment was associated with mean increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic and an increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg compared to placebo. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment (see ADVERSE REACTIONS, Vital Sign Changes). Activation of Mania/Hypomania — In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (1/1139) of Cymbalta-treated patients and 0.1% (1/777) of placebo-treated patients. Activation of mania/hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Cymbalta should be used cautiously in patients with a history of mania. Seizures — Cymbalta has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials in patients with major depressive disorder, seizures occurred in 0.1% (1/1139) of patients treated with Cymbalta and 0% (0/777) of patients treated with placebo. In placebo-controlled clinical trials in patients with diabetic peripheral neuropathy, seizures did not occur in any patients treated with either Cymbalta or placebo. Cymbalta should be prescribed with care in patients with a history of a seizure disorder. Controlled Narrow-Angle Glaucoma — In clinical trials, Cymbalta was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma (see CONTRAINDICATIONS, Uncontrolled Narrow-Angle Glaucoma). Discontinuation of Treatment with Cymbalta — Discontinuation symptoms have been systematically evaluated in patients taking Cymbalta. Following abrupt discontinuation in MDD placebo-controlled clinical trials of up to 9-weeks duration, the following symptoms occurred at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness; nausea; headache; paresthesia; vomiting; irritability; and nightmare. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Use in Patients with Concomitant Illness — Clinical experience with Cymbalta in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Cymbalta’s enteric coating. As duloxetine is rapidly hydrolyzed in acidic media to naphthol, caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Cymbalta has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing. However, the electrocardiograms of 321 patients who received Cymbalta in MDD placebo-controlled clinical trials and had qualitatively normal ECGs at baseline were evaluated; Cymbalta was not associated with the development of clinically significant ECG abnormalities (see ADVERSE REACTIONS, Electrocardiogram Changes). In DPN placebo-controlled clinical trials, Cymbalta-treated patients did not develop abnormal ECGs at a rate different from that in placebo-treated patients (see ADVERSE REACTIONS, Electrocardiogram Changes). In three clinical trials of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, small increases in fasting blood glucose were observed in Cymbalta-treated patients. HbA1c was stable in both Cymbalta-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the Cymbalta and the routine care groups, but the mean increase was 0.3% greater in the Cymbalta-treated group. There was also a small increase in fasting blood glucose in the Cymbalta-treated group. Total cholesterol was increased in Cymbalta-treated patients (2 mg/dL) and decreased in the routine care group (6 mg/dL). Increased plasma concentrations of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis). For this reason, Cymbalta is not recommended for patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Markedly increased exposure to duloxetine occurs in patients with hepatic insufficiency and Cymbalta should not be administered to these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Cymbalta and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Cymbalta. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Cymbalta. Clinical Worsening and Suicide Risk — Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Cymbalta should be swallowed whole and should not be chewed or crushed, nor should the contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Cymbalta has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, patients should be cautioned about operating hazardous machinery including automobiles, until they are reasonably certain that Cymbalta therapy does not affect their ability to engage in such activities. Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions. Although Cymbalta does not increase the impairment of mental and motor skills caused by alcohol, use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should ordinarily not be prescribed for patients with substantial alcohol use. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Cymbalta and triptans, tramadol or other serotonergic agents. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast-feeding. While patients with MDD may notice improvement with Cymbalta therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Laboratory Tests No specific laboratory tests are recommended. Drug Interactions (also see CLINICAL PHARMACOLOGY, Drug-Drug Interactions) Potential for Other Drugs to Affect Cymbalta Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Inhibitors of CYP1A2 — Concomitant use of duloxetine with fluvoxamine, an inhibitor of CYP1A2, results in approximately a 6-fold increase in AUC and about a 2.5-fold increase in Cmax of duloxetine. Some quinolone antibiotics would be expected to have similar effects and these combinations should be avoided. Inhibitors of CYP2D6 — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 may result in higher concentrations of duloxetine. Paroxetine (20 mg QD) increased the concentration of duloxetine (40 mg QD) by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine). Potential for Duloxetine to Affect Other Drugs Drugs Metabolized by CYP1A2 — In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity, and it is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates (see CLINICAL PHARMACOLOGY, Drug Interactions). Drugs Metabolized by CYP2D6 — Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg BID) in conjunction with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. Therefore, co-administration of Cymbalta with other drugs that are extensively metabolized by this isozyme and which have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Cymbalta. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Cymbalta and thioridazine should not be co-administered. Drugs Metabolized by CYP3A — Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity (see CLINICAL PHARMACOLOGY, Drug Interactions). Cymbalta May Have a Clinically Important Interaction with the Following Other Drugs: Alcohol — When Cymbalta and ethanol were administered several hours apart so that peak concentrations of each would coincide, Cymbalta did not increase the impairment of mental and motor skills caused by alcohol. In the Cymbalta clinical trials database, three Cymbalta-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen (see PRECAUTIONS, Hepatotoxicity). CNS Acting Drugs — Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Serotonergic Drugs — Based on the mechanism of action of Cymbalta and the potential for serotonin syndrome, caution is advised when Cymbalta is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS, Serotonin Syndrome). The concomitant use of Cymbalta with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS, Drug Interactions). Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Potential for Interaction with Drugs that Affect Gastric Acidity — Cymbalta has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of Cymbalta with aluminum- and magnesium-containing antacids (51 mEq) or Cymbalta with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40-mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption. Monoamine Oxidase Inhibitors — See CONTRAINDICATIONS and WARNINGS. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis — Duloxetine was administered in the diet to mice and rats for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis). In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors. Mutagenesis — Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo. Impairment of Fertility — Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Pregnancy Pregnancy Category C — In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the human dose of 120 mg/day on a mg/m2 basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m2 basis in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and ≈1 times the human dose of 120 mg/day on a mg/m2 basis in rat; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects — Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS, Monoamine Oxidase Inhibitors). When treating a pregnant woman with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use Of the 2418 patients in clinical studies of Cymbalta for MDD, 5.9% (143) were 65 years of age or over. Of the 1074 patients in the DPN studies, 33% (357) were 65 years of age or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Cymbalta has been evaluated for safety in 2418 patients diagnosed with major depressive disorder who participated in multiple-dose premarketing trials, representing 1099 patient-years of exposure. Among these 2418 Cymbalta-treated patients, 1139 patients participated in eight 8- or 9-week, placebo-controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1 year in an open-label safety study using flexible doses from 80 to 120 mg/day. Two placebo-controlled studies with doses of 80 and 120 mg/day had 6-month maintenance extensions. Of these 2418 patients, 993 Cymbalta-treated patients were exposed for at least 180 days and 445 Cymbalta-treated patients were exposed for at least 1 year. Cymbalta has also been evaluated for safety in 1074 patients with diabetic peripheral neuropathy representing 472 patient-years of exposure. Among these 1074 Cymbalta-treated patients, 568 patients participated in two 12- to 13-week, placebo-controlled trials at doses ranging from 20 to 120 mg/day. An additional 449 patients were enrolled in an open-label safety study using 120 mg/day for a duration of 6 months. Another 57 patients, originally treated with placebo, were exposed to Cymbalta for up to 12 months at 60 mg twice daily in an extension phase. Among these 1074 patients, 484 had 6 months of exposure to Cymbalta, and 220 had 12 months of exposure. For both MDD and DPN clinical trials, adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. Clinical investigators recorded adverse events using descriptive terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, grouping similar types of events into a smaller number of standardized event categories is necessary. In the tables and tabulations that follow, MedDRA terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Events reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality. The cited figures provide the prescriber with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Major Depressive Disorder Approximately 10% of the 1139 patients who received Cymbalta in the MDD placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients receiving placebo. Nausea (Cymbalta 1.4%, placebo 0.1%) was the only common adverse event reported as reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo). Diabetic Peripheral Neuropathic Pain Approximately 14% of the 568 patients who received Cymbalta in the DPN placebo-controlled trials discontinued treatment due to an adverse event, compared with 7% of the 223 patients receiving placebo. Nausea (Cymbalta 3.5%, placebo 0.4%), dizziness (Cymbalta 1.6%, placebo 0.4%), somnolence (Cymbalta 1.6%, placebo 0%) and fatigue (Cymbalta 1.1%, placebo 0%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo). Adverse Events Occurring at an Incidence of 2% or More Among Cymbalta- Treated Patients in Placebo-Controlled Trials Major Depressive Disorder Table 1 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of MDD placebo-controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated MDD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; dry mouth; constipation; decreased appetite; fatigue; somnolence; and increased sweating (see Table 1). Table 1: Treatment-Emergent Adverse Events Incidence in MDD Placebo-Controlled Trials1 Percentage of Patients Reporting Event System Organ Class / Adverse Event Cymbalta (N=1139) Placebo (N=777) Gastrointestinal Disorders Nausea 20 7 Dry mouth 15 6 Constipation 11 4 Diarrhea 8 6 Vomiting 5 3 Metabolism and Nutrition Disorders Appetite decreased2 8 2 Investigations Weight decreased 2 1 General Disorders and Administration Site Conditions This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Fatigue 8 4 Nervous System Disorders Dizziness 9 5 Somnolence 7 3 Tremor 3 1 Skin and Subcutaneous Tissue Disorders Sweating increased 6 2 Vascular Disorders Hot flushes 2 1 Eye Disorders Vision blurred 4 1 Psychiatric Disorders Insomnia3 11 6 Anxiety 3 2 Libido decreased 3 1 Orgasm abnormal4 3 1 Reproductive System and Breast Disorders Erectile dysfunction5 4 1 Ejaculation delayed5 3 1 Ejaculatory dysfunction5, 6 3 1 1 Events reported by at least 2% of patients treated with Cymbalta and more often with placebo. The following events were reported by at least 2% of patients treated with Cymbalta for MDD and had an incidence equal to or less than placebo: upper abdominal pain, palpitations, dyspepsia, back pain, arthralgia, headache, pharyngitis, cough, nasopharyngitis, and upper respiratory tract infection. 2 Term includes anorexia. 3 Term includes middle insomnia. 4 Term includes anorgasmia. 5 Male patients only. 6 Term includes ejaculation disorder and ejaculation failure. Diabetic Peripheral Neuropathic Pain Table 2 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of DPN placebo-controlled trials (doses of 20 to 120 mg/day) and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated DPN patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; somnolence; dizziness; constipation; dry mouth; hyperhidrosis; decreased appetite; and asthenia (see Table 2). Table 2: Treatment-Emergent Adverse Events Incidence in DPN Placebo-Controlled Trials1 Percentage of Patients Reporting Event System Organ Class / Adverse Event Cymbalta 60 mg BID (N=225) Cymbalta 60 mg QD (N=228) Cymbalta 20 mg QD (N=115) Placebo (N=223) Gastrointestinal Disorders Nausea 30 22 14 9 Constipation 15 11 5 3 Diarrhea 7 11 13 6 Dry mouth 12 7 5 4 Vomiting 5 5 6 4 Dyspepsia 4 4 4 3 Loose stools 2 3 2 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 General Disorders and Administration Site Conditions Fatigue 12 10 2 5 Asthenia 8 4 2 1 Pyrexia 3 1 2 1 Infections and Infestations Nasopharyngitis 9 7 9 5 Metabolism and Nutrition Disorders Decreased appetite 11 4 3 <1 Anorexia 5 3 3 <1 Musculoskeletal and Connective Tissue Disorders Muscle cramp 4 4 5 3 Myalgia 4 1 3 <1 Nervous System Disorders Somnolence 21 15 7 5 Headache 15 13 13 10 Dizziness 17 14 6 6 Tremor 5 1 0 0 Psychiatric Disorders Insomnia 13 8 9 7 Renal and Urinary Disorders Pollakiuria 5 1 3 2 Reproductive System and Breast Disorders Erectile dysfunction2 4 1 0 0 Respiratory, Thoracic and Mediastinal Disorders Cough 5 3 6 4 Pharyngolaryngeal pain 6 1 3 1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 8 6 6 2 1 Events reported by at least 2% of patients treated with Cymbalta and more often than placebo. The following events were reported by at least 2% of patients treated with Cymbalta for DPN and had an incidence equal to or less than placebo: edema peripheral, influenza, upper respiratory tract infection, back pain, arthralgia, pain in extremity, and pruritus. 2 Male patients only. Adverse events seen in men and women were generally similar except for effects on sexual function (described below). Clinical studies of Cymbalta did not suggest a difference in adverse event rates in people over or under 65 years of age. There were too few non-Caucasian patients studied to determine if these patients responded differently from Caucasian patients. Effects on Male and Female Sexual Function Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Table 3 displays the incidence of sexual side effects This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 spontaneously reported by at least 2% of either male or female patients taking Cymbalta in MDD placebo-controlled trials. Table 3: Treatment-Emergent Sexual Dysfunction-Related Adverse Events Incidence in MDD Placebo-Controlled Trials1 Percentage of Patients Reporting Event % Male Patients % Female Patients Adverse Event Cymbalta (N=378) Placebo (N=247) Cymbalta (N=761) Placebo (N=530) Orgasm abnormal2 4 1 2 0 Ejaculatory dysfunction3 3 1 NA NA Libido decreased 6 2 1 0 Erectile dysfunction 4 1 NA NA Ejaculation delayed 3 1 NA NA 1 Events reported by at least 2% of patients treated with Cymbalta and more often than with placebo. 2 Term includes anorgasmia. 3 Term includes ejaculation disorder and ejaculation failure. NA=Not applicable. Because adverse sexual events are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 4 below, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score. These studies did not, however, include an active control drug with known effects on female sexual dysfunction, so that there is no evidence that its effects differ from other antidepressants. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects. Table 4: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials Male Patients Female Patients Cymbalta (n=175) Placebo (n=83) Cymbalta (n=241) Placebo (n=126) ASEX Total (Items 1-5) 0.56* -1.07 -1.15 -1.07 Item 1 — Sex drive -0.07 -0.12 -0.32 -0.24 Item 2 — Arousal 0.01 -0.26 -0.21 -0.18 Item 3 — Ability to achieve erection (men); Lubrication (women) 0.03 -0.25 -0.17 -0.18 Item 4 — Ease of reaching orgasm 0.40** -0.24 -0.09 -0.13 Item 5 — Orgasm satisfaction 0.09 -0.13 -0.11 -0.17 n=Number of patients with non-missing change score for ASEX total. * p=0.013 versus placebo. ** p<0.001 versus placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 Urinary Hesitation Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related. Laboratory Changes Cymbalta treatment, for up to 9-weeks in MDD or 13-weeks in DPN placebo-controlled clinical trials, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Cymbalta-treated patients when compared with placebo-treated patients (see PRECAUTIONS). Vital Sign Changes Cymbalta treatment, for up to 9-weeks in MDD placebo-controlled clinical trials of 40 to 120 mg daily doses caused increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic compared to placebo and an increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg (see PRECAUTIONS). Cymbalta treatment, for up to 9-weeks in MDD placebo-controlled clinical trials and for up to 13-weeks in DPN placebo-controlled trials caused a small increase in heart rate compared to placebo of about 2 beats per minute. Weight Changes In MDD placebo-controlled clinical trials, patients treated with Cymbalta for up to 9-weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In DPN placebo-controlled clinical trials, patients treated with Cymbalta for up to 13-weeks experienced a mean weight loss of approximately 1.1 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. Electrocardiogram Changes Electrocardiograms were obtained from 321 Cymbalta-treated patients with major depressive disorder and 169 placebo-treated patients in clinical trials lasting up to 8-weeks. The rate-corrected QT (QTc) interval in Cymbalta-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, and QRS intervals between Cymbalta-treated and placebo-treated patients. Electrocardiograms were obtained from 528 Cymbalta-treated patients with DPN and 205 placebo-treated patients in clinical trials lasting up to 13-weeks. The rate-corrected QT (QTc) interval in Cymbalta-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTc measurements between Cymbalta-treated and placebo-treated patients. Other Adverse Events Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Cymbalta for MDD and the Pain of DPN Following is a list of modified MedDRA terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with Cymbalta at multiple doses throughout the dose range studied during any phase of a trial within the premarketing and postmarketing database. The events included are those not already listed in both Table 1 and Table 2 and not considered in the WARNINGS and PRECAUTIONS sections. The events were reported with an incidence of greater than or equal to 0.05% and by more than one patient, are not common as background events and were This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 considered possibly drug related (e.g., because of the drug’s pharmacology) or potentially important. It is important to emphasize that, although the events reported occurred during treatment with Cymbalta, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Blood and Lymphatic System Disorders — Infrequent: anemia, leukopenia, increased white blood cell count, lymphadenopathy, and thrombocytopenia. Cardiac Disorders — Frequent: palpitations; Infrequent: atrial fibrillation, bundle branch block right, cardiac failure, cardiac failure congestive, coronary artery disease, myocardial infarction, and tachycardia. Ear and Labyrinth Disorders — Frequent: vertigo. Eye Disorders — Frequent: vision blurred; Infrequent: diplopia, glaucoma, keroconjunctivitis sicca, macular degeneration, maculopathy, photopsia, retinal detachment, and visual disturbance. Gastrointestinal Disorders — Frequent: dyspepsia and gastritis; Infrequent: apthous stomatitis, blood in stool, colitis, diverticulitis, dysphagia, eructation, esophageal stenosis acquired, gastric irritation, gastric ulcer, gastroenteritis, gingivitis, impaired gastric emptying, irritable bowel syndrome, lower abdominal pain, melena, and stomatitis. General Disorders and Administration Site Conditions — Frequent: asthenia; Infrequent: edema, feeling abnormal, feeling hot and/or cold, feeling jittery, influenza-like illness, malaise, rigors, and thirst. Hepato-biliary Disorders — Infrequent: hepatic steatosis. Investigations — Frequent: weight decreased; Infrequent: blood cholesterol increased, blood creatinine increased, urine output decreased, and weight increased. Metabolism and Nutrition Disorders — Frequent: hypoglycemia and increased appetite; Infrequent: dehydration, dyslipidemia, hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia. Musculoskeletal and Connective Tissue Disorders — Frequent: muscle tightness and muscle twitching; Infrequent: muscular weakness. Nervous System Disorders — Frequent: dysgeusia and hypoesthesia; Infrequent: ataxia and dysarthria. Psychiatric Disorders — Frequent: anorgasmia, anxiety, hypersomnia, initial insomnia, irritability, lethargy, libido decreased, middle insomnia, nervousness, nightmare, restlessness, and sleep disorder; Infrequent: agitation, bruxism, completed suicide, disorientation, loss of libido, mania, mood swings, orgasm abnormal, pressure of speech, sluggishness, suicide attempt, and tension. Renal and Urinary Disorders — Frequent: dysuria and urinary hesitation; Infrequent: micturition urgency, nephropathy, nocturia, urinary incontinence, urinary retention, and urine flow decreased. Reproductive System and Breast Disorders — Frequent: ejaculation delayed and ejaculation disorder. Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning; Infrequent: oropharyngeal swelling. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Skin and Subcutaneous Tissue Disorders — Frequent: night sweats, pruritus, rash, and skin ulcer; Infrequent: acne, alopecia, cold sweat, ecchymosis, eczema, erythema, erythematous rash, exfoliative dermatitis, face edema, hyperkeratosis, increased tendency to bruise, photosensitivity reaction, and pruritic rash. Vascular Disorders — Frequent: hot flush; Infrequent: flushing, hypertensive crisis, peripheral coldness, peripheral edema, and phlebitis. Postmarketing Spontaneous Reports Adverse events reported rarely since market introduction that were temporally related to Cymbalta therapy include: hallucinations, rash, and urinary retention. The following adverse events were reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, extrapyramidal disorder, glaucoma, hepatitis, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), serotonin syndrome, Stevens-Johnson Syndrome, syncope (especially at initiation of treatment), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and urticaria. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Duloxetine is not a controlled substance. Physical and Psychological Dependence In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential. In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats. While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Cymbalta (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE There is limited clinical experience with Cymbalta overdose in humans. In premarketing clinical trials, cases of acute ingestions up to 1400 mg, alone or in combination with other drugs, were reported with none being fatal. Postmarketing experience includes reports of overdoses, alone or in combination with other drugs, with duloxetine doses of almost 2000 mg. Fatalities have been very rarely reported, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (mostly with mixed drugs) included serotonin syndrome, somnolence, vomiting, and seizures. Management of Overdose There is no specific antidote to Cymbalta, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Cymbalta and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS, Drug Interactions). The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). DOSAGE AND ADMINISTRATION Initial Treatment Major Depressive Disorder Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg BID) to 60 mg/day (given either once a day or as 30 mg BID) without regard to meals. There is no evidence that doses greater than 60 mg/day confer any additional benefits. Diabetic Peripheral Neuropathic Pain Cymbalta should be administered at a total dose of 60 mg/day given once a day, without regard to meals. While a 120 mg/day dose was shown to be safe and effective, there is no evidence that doses higher than 60 mg confer additional significant benefit, and the higher dose is clearly less well tolerated. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment (see CLINICAL PHARMACOLOGY, Special Populations and below). Maintenance/Continuation/Extended Treatment Major Depressive Disorder It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. There is insufficient evidence available to answer the question of how long a patient should continue to be treated with Cymbalta. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Diabetic Peripheral Neuropathic Pain As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials, but a one-year open-label safety study was conducted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 Special Populations Dosage for Renally Impaired Patients — Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or in severe renal impairment (estimated creatinine clearance <30 mL/min) (see CLINICAL PHARMACOLOGY). Dosage for Hepatically Impaired Patients — It is recommended that Cymbalta not be administered to patients with any hepatic insufficiency (see CLINICAL PHARMACOLOGY and PRECAUTIONS). Dosage for Elderly Patients — No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose. Treatment of Pregnant Women During the Third Trimester — Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cymbalta in the third trimester. Dosage for Nursing Mothers — Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics (see CLINICAL PHARMACOLOGY). Discontinuing Cymbalta Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Switching Patients to or from a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI (see CONTRAINDICATIONS and WARNINGS). HOW SUPPLIED Cymbalta® (duloxetine hydrochloride) Delayed-release Capsules are available in 20, 30, and 60 mg strengths. The 20 mg* capsule has an opaque green body and cap, and is imprinted with “20 mg” on the body and “LILLY 3235” on the cap: NDC 0002-3235-60 (PU3235) — Bottles of 60 NDC 0002-3235-33 (PU3235) — (ID†100) Blisters The 30 mg* capsule has an opaque white body and opaque blue cap, and is imprinted with “30 mg” on the body and “LILLY 3240” on the cap: NDC 0002-3240-30 (PU3240) — Bottles of 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 NDC 0002-3240-90 (PU3240) — Bottles of 90 NDC 0002-3240-04 (PU3240) — Bottles of 1000 NDC 0002-3240-33 (PU3240) — (ID†100) Blisters The 60 mg* capsule has an opaque green body and opaque blue cap, and is imprinted with “60 mg” on the body and “LILLY 3237” on the cap: NDC 0002-3237-30 (PU3237) — Bottles of 30 NDC 0002-3237-90 (PU3237) — Bottles of 90 NDC 0002-3237-04 (PU3237) — Bottles of 1000 NDC 0002-3237-33 (PU3237) — (ID†100) Blisters * equivalent to duloxetine base. † Identi-Dose® (unit dose medication, Lilly). Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Literature revised August 22, 2006 Eli Lilly and Company Indianapolis, IN 46285, USA www.Cymbalta.com Copyright © 2004, 2006, Eli Lilly and Company. All rights reserved. PV 3607 AMP PRINTED IN USA PV 5081 AMP Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your health care provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child’s life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. Whenever an antidepressant is started or its dose is changed, pay close attention to your child. After starting an antidepressant, your child should generally see his or her health care provider • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your health care provider’s advice about how often to come back • More often if problems or questions arise (see Section 3) You should call your child’s health care provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child’s health care provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child’s teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her health care provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your health care provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®). Your health care provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your health care provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your health care provider or pharmacist where to find more information. Prozac® is a registered trademark of Eli Lilly and Company. Zoloft® is a registered trademark of Pfizer Pharmaceuticals. Anafranil® is a registered trademark of Mallinckrodt Inc. This Medication Guide has been approved by the US Food and Drug Administration for all antidepressants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 PV 3607 AMP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:45.049731	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018936s76,20101s35,20974s8,21235s7,21520s12,21427s11lbl.pdf', 'application_number': 20101, 'submission_type': 'SUPPL ', 'submission_number': 35}
12,216	PRESCRIBING INFORMATION ZOFRAN® (ondansetron hydrochloride) Tablets ZOFRAN ODT® (ondansetron) Orally Disintegrating Tablets ZOFRAN® (ondansetron hydrochloride) Oral Solution DESCRIPTION The active ingredient in ZOFRAN Tablets and ZOFRAN Oral Solution is ondansetron hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1- yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula: The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9. Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal saline. The active ingredient in ZOFRAN ODT Orally Disintegrating Tablets is ondansetron base, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one. It has the following structural formula: The empirical formula is C18H19N3O representing a molecular weight of 293.4. Each 4-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. Each 8-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, pregelatinized starch, hypromellose, magnesium stearate, titanium dioxide, triacetin, and iron oxide yellow (8-mg tablet only). Each 4-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 4 mg ondansetron base. Each 8-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 8 mg ondansetron base. Each ZOFRAN ODT Tablet also contains the inactive ingredients This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda aspartame, gelatin, mannitol, methylparaben sodium, propylparaben sodium, and strawberry flavor. ZOFRAN ODT Tablets are a freeze-dried, orally administered formulation of ondansetron which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. Each 5 mL of ZOFRAN Oral Solution contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. ZOFRAN Oral Solution contains the inactive ingredients citric acid anhydrous, purified water, sodium benzoate, sodium citrate, sorbitol, and strawberry flavor. CLINICAL PHARMACOLOGY Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting reflex. In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT3 receptor antagonist. In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied. Pharmacokinetics: Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%. Ondansetron systemic exposure does not increase proportionately to dose. AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. Bioavailability is also slightly enhanced by the presence of food but unaffected by antacids. Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½ of ondansetron was observed.1 This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended (see PRECAUTIONS: Drug Interactions). In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 1 and 2 taken from 2 studies. Table 1. Pharmacokinetics in Normal Volunteers: Single 8-mg ZOFRAN Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) Systemic Plasma Clearance L/h/kg Absolute Bioavailability 18-40 M F 69.0 62.7 6 5 26.2 42.7 2.0 1.7 3.1 3.5 0.403 0.354 0.483 0.663 61-74 M F 77.5 60.2 6 6 24.1 52.4 2.1 1.9 4.1 4.9 0.384 0.255 0.585 0.643 ≥75 M F 78.0 67.6 5 6 37.0 46.1 2.2 2.1 4.5 6.2 0.277 0.249 0.619 0.747 Table 2. Pharmacokinetics in Normal Volunteers: Single 24-mg ZOFRAN Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) 18-43 M F 84.1 71.8 8 8 125.8 194.4 1.9 1.6 4.7 5.8 A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy was similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly. In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded. Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron oral mean plasma clearance was reduced by about 50% in patients with severe renal impairment (creatinine clearance <30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted. Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes. Four- and 8-mg doses of either ZOFRAN Oral Solution or ZOFRAN ODT Orally Disintegrating Tablets are bioequivalent to corresponding doses of ZOFRAN Tablets and may be used interchangeably. One 24-mg ZOFRAN Tablet is bioequivalent to and interchangeable with three 8-mg ZOFRAN Tablets. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL TRIALS Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 randomized, double-blind, monotherapy trials, a single 24-mg ZOFRAN Tablet was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose ≥50 mg/m2 in the historical placebo comparator experienced vomiting in the absence of antiemetic therapy. The first trial compared oral doses of ondansetron 24 mg once a day, 8 mg twice a day, and 32 mg once a day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin ≥50 mg/m2. A total of 66% of patients in the ondansetron 24-mg once-a-day group, 55% in the ondansetron 8-mg twice-a-day group, and 55% in the ondansetron 32-mg once-a-day group completed the 24-hour study period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control. In the same trial, 56% of patients receiving oral ondansetron 24 mg once a day experienced no nausea during the 24-hour study period, compared with 36% of patients in the oral ondansetron 8-mg twice-a- day group (p = 0.001) and 50% in the oral ondansetron 32-mg once-a-day group. In a second trial, efficacy of the oral ondansetron 24-mg once-a-day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m2, was confirmed. Moderately Emetogenic Chemotherapy: In 1 double-blind US study in 67 patients, ZOFRAN Tablets 8 mg administered twice a day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 3: Table 3. Emetic Episodes: Treatment Response Ondansetron 8-mg b.i.d. ZOFRAN Tablets* Placebo p Value Number of patients 33 34 Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn 20 (61%) 6 (18%) 7 (21%) 2 (6%) 8 (24%) 24 (71%) <0.001 <0.001 Median number of emetic episodes 0.0 Undefined† Median time to first emetic episode (h) Undefined‡ 6.5 * The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered twice a day for 2 days after completion of chemotherapy. † Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. ‡ Median undefined since at least 50% of patients did not have any emetic episodes. In 1 double-blind US study in 336 patients, ZOFRAN Tablets 8 mg administered twice a day were as effective as ZOFRAN Tablets 8 mg administered 3 times a day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 4: Table 4. Emetic Episodes: Treatment Response Ondansetron 8-mg b.i.d. ZOFRAN Tablets* 8-mg t.i.d. ZOFRAN Tablets† Number of patients 165 171 Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn 101 (61%) 16 (10%) 48 (29%) 99 (58%) 17 (10%) 55 (32%) Median number of emetic episodes 0.0 0.0 Median time to first emetic episode (h) Undefined‡ Undefined‡ Median nausea scores (0-100)§ 6 6 * The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered twice a day for 2 days after completion of chemotherapy. † The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered 3 times a day for 2 days after completion of chemotherapy. ‡ Median undefined since at least 50% of patients did not have any emetic episodes. § Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be. Re-treatment: In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ZOFRAN Tablets 8 mg 3 times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the re-treatment courses. Pediatric Studies: Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients 4 to 18 years old with cancer who were given a variety of cisplatin or noncisplatin regimens. In these foreign trials, the initial dose of ZOFRAN® (ondansetron HCl) Injection ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the administration of ZOFRAN Tablets ranging from 4 to 24 mg daily for 3 days. In these studies, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received ZOFRAN Tablets 4 mg 3 times a day to be similar to those in patients 12 to 18 years of age who received ZOFRAN Tablets 8 mg 3 times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, ZOFRAN Tablets were well tolerated in these pediatric patients. Radiation-Induced Nausea and Vomiting: Total Body Irradiation: In a randomized, double-blind study in 20 patients, ZOFRAN Tablets (8 mg given 1.5 hours before each fraction of radiotherapy for 4 days) were significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 2 fractions on day 4. Single High-Dose Fraction Radiotherapy: Ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of ≥80 cm2 to the abdomen. Patients received the first dose of ZOFRAN Tablets (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 2 additional doses of study treatment were given (1 tablet late afternoon and 1 tablet before bedtime). If This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda radiotherapy was given in the afternoon, patients took only 1 further tablet that day before bedtime. Patients continued the oral medication on a 3 times a day basis for 3 days. Daily Fractionated Radiotherapy: Ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 135 patients receiving a 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over a field size of ≥100 cm2 to the abdomen. Patients received the first dose of ZOFRAN Tablets (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the patient received the first daily radiotherapy fraction, with 2 subsequent doses on a 3 times a day basis. Patients continued the oral medication on a 3 times a day basis on each day of radiotherapy. Postoperative Nausea and Vomiting: Surgical patients who received ondansetron 1 hour before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; and supplemental isoflurane or enflurane) were evaluated in 2 double-blind studies (1 US study, 1 foreign) involving 865 patients. ZOFRAN Tablets (16 mg) were significantly more effective than placebo in preventing postoperative nausea and vomiting. The study populations in all trials thus far consisted of women undergoing inpatient surgical procedures. No studies have been performed in males. No controlled clinical study comparing ZOFRAN Tablets to ZOFRAN Injection has been performed. INDICATIONS AND USAGE 1. Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m2. 2. Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. 3. Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen. 4. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, and ZOFRAN Oral Solution are recommended even where the incidence of postoperative nausea and/or vomiting is low. CONTRAINDICATIONS ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, and ZOFRAN Oral Solution are contraindicated for patients known to have hypersensitivity to the drug. WARNINGS Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. PRECAUTIONS General: Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients: Phenylketonurics: Phenylketonuric patients should be informed that ZOFRAN ODT Orally Disintegrating Tablets contain phenylalanine (a component of aspartame). Each 4-mg and 8-mg orally disintegrating tablet contains <0.03 mg phenylalanine. Patients should be instructed not to remove ZOFRAN ODT Tablets from the blister until just prior to dosing. The tablet should not be pushed through the foil. With dry hands, the blister backing should be peeled completely off the blister. The tablet should be gently removed and immediately placed on the tongue to dissolve and be swallowed with the saliva. Peelable illustrated stickers are affixed to the product carton that can be provided with the prescription to ensure proper use and handling of the product. Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P-388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high- dose methotrexate. Use in Surgical Patients: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg/day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg/day did not affect fertility or general reproductive performance of male and female rats. Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman. Pediatric Use: Little information is available about dosage in pediatric patients 4 years of age or younger (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION sections for use in pediatric patients 4 to 18 years of age). Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there were subgroup analyses, 938 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL PHARMACOLOGY). ADVERSE REACTIONS The following have been reported as adverse events in clinical trials of patients treated with ondansetron, the active ingredient of ZOFRAN. A causal relationship to therapy with ZOFRAN has been unclear in many cases. Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 5 have been reported in ≥5% of adult patients receiving a single 24-mg ZOFRAN Tablet in 2 trials. These patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens (cisplatin dose ≥50 mg/m2). Table 5. Principal Adverse Events in US Trials: Single Day Therapy With 24-mg ZOFRAN Tablets (Highly Emetogenic Chemotherapy) Event Ondansetron 24 mg q.d. n = 300 Ondansetron 8 mg b.i.d. n = 124 Ondansetron 32 mg q.d. n = 117 Headache 33 (11%) 16 (13%) 17 (15%) Diarrhea 13 (4%) 9 (7%) 3 (3%) The adverse events in Table 6 have been reported in ≥5% of adults receiving either 8 mg of ZOFRAN Tablets 2 or 3 times a day for 3 days or placebo in 4 trials. These patients were receiving concurrent moderately emetogenic chemotherapy, primarily cyclophosphamide-based regimens. Table 6. Principal Adverse Events in US Trials: 3 Days of Therapy With 8-mg ZOFRAN Tablets (Moderately Emetogenic Chemotherapy) Event Ondansetron 8 mg b.i.d. n = 242 Ondansetron 8 mg t.i.d. n = 415 Placebo n = 262 Headache 58 (24%) 113 (27%) 34 (13%) Malaise/fatigue 32 (13%) 37 (9%) 6 (2%) Constipation 22 (9%) 26 (6%) 1 (<1%) Diarrhea 15 (6%) 16 (4%) 10 (4%) Dizziness 13 (5%) 18 (4%) 12 (5%) Central Nervous System: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron. Hepatic: In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in approximately 1% to 2% of patients receiving ZOFRAN Tablets. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes cannot be clearly determined. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron. Other: Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures have been reported. Except for bronchospasm and anaphylaxis, the relationship to ZOFRAN was unclear. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Radiation-Induced Nausea and Vomiting: The adverse events reported in patients receiving ZOFRAN Tablets and concurrent radiotherapy were similar to those reported in patients receiving ZOFRAN Tablets and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea. Postoperative Nausea and Vomiting: The adverse events in Table 7 have been reported in ≥5% of patients receiving ZOFRAN Tablets at a dosage of 16 mg orally in clinical trials. With the exception of headache, rates of these events were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications. Table 7. Frequency of Adverse Events From Controlled Studies With ZOFRAN Tablets (Postoperative Nausea and Vomiting) Adverse Event Ondansetron 16 mg (n = 550) Placebo (n = 531) Wound problem 152 (28%) 162 (31%) Drowsiness/sedation 112 (20%) 122 (23%) Headache 49 (9%) 27 (5%) Hypoxia 49 (9%) 35 (7%) Pyrexia 45 (8%) 34 (6%) Dizziness 36 (7%) 34 (6%) Gynecological disorder 36 (7%) 33 (6%) Anxiety/agitation 33 (6%) 29 (5%) Bradycardia 32 (6%) 30 (6%) Shiver(s) 28 (5%) 30 (6%) Urinary retention 28 (5%) 18 (3%) Hypotension 27 (5%) 32 (6%) Pruritus 27 (5%) 20 (4%) Preliminary observations in a small number of subjects suggest a higher incidence of headache when ZOFRAN ODT Orally Disintegrating Tablets are taken with water, when compared to without water. Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of ZOFRAN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ZOFRAN. Cardiovascular: Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron. Hepatobiliary: Liver enzyme abnormalities Lower Respiratory: Hiccups Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions Skin: Urticaria Special Senses: Eye Disorders: Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DRUG ABUSE AND DEPENDENCE Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies. OVERDOSAGE There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose. In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in 1 patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of ZOFRAN Tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely. DOSAGE AND ADMINISTRATION Instructions for Use/Handling ZOFRAN ODT Orally Disintegrating Tablets: Do not attempt to push ZOFRAN ODT Tablets through the foil backing. With dry hands, PEEL BACK the foil backing of 1 blister and GENTLY remove the tablet. IMMEDIATELY place the ZOFRAN ODT Tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary. Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy: The recommended adult oral dosage of ZOFRAN is 24 mg given as three 8-mg tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥50 mg/m2. Multiday, single-dose administration of a 24 mg dosage has not been studied. Pediatric Use: There is no experience with the use of a 24 mg dosage in pediatric patients. Geriatric Use: The dosage recommendation is the same as for the general population. Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy: The recommended adult oral dosage is one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. Pediatric Use: For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4-mg ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ZOFRAN Oral Solution given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4-mg ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ZOFRAN Oral Solution should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy. Geriatric Use: The dosage is the same as for the general population. Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen: The recommended oral dosage is one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution given 3 times a day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For total body irradiation, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before each fraction of radiotherapy administered each day. For single high-dose fraction radiotherapy to the abdomen, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. For daily fractionated radiotherapy to the abdomen, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given. Pediatric Use: There is no experience with the use of ZOFRAN Tablets, ZOFRAN ODT Tablets, or ZOFRAN Oral Solution in the prevention of radiation-induced nausea and vomiting in pediatric patients. Geriatric Use: The dosage recommendation is the same as for the general population. Postoperative Nausea and Vomiting: The recommended dosage is 16 mg given as two 8-mg ZOFRAN Tablets or two 8-mg ZOFRAN ODT Tablets or 20 mL (4 teaspoonfuls equivalent to 16 mg of ondansetron) of ZOFRAN Oral Solution 1 hour before induction of anesthesia. Pediatric Use: There is no experience with the use of ZOFRAN Tablets, ZOFRAN ODT Tablets, or ZOFRAN Oral Solution in the prevention of postoperative nausea and vomiting in pediatric patients. Geriatric Use: The dosage is the same as for the general population. Dosage Adjustment for Patients With Impaired Renal Function: The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron. Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a total daily dose of 8 mg should not be exceeded. HOW SUPPLIED ZOFRAN Tablets, 4 mg (ondansetron HCl dihydrate equivalent to 4 mg of ondansetron), are white, oval, film-coated tablets engraved with "Zofran" on one side and "4" on the other in daily unit dose packs of 3 tablets (NDC 0173-0446-04), bottles of 30 tablets (NDC 0173-0446-00), and unit dose packs of 100 tablets (NDC 0173-0446-02). Bottles: Store between 2° and 30°C (36° and 86°F). Protect from light. Dispense in tight, light- resistant container as defined in the USP. Unit Dose Packs: Store between 2° and 30°C (36° and 86°F). Protect from light. Store blisters in cartons. ZOFRAN Tablets, 8 mg (ondansetron HCl dihydrate equivalent to 8 mg of ondansetron), are yellow, oval, film-coated tablets engraved with "Zofran" on one side and "8" on the other in daily unit dose packs of 3 tablets (NDC 0173-0447-04), bottles of 30 tablets (NDC 0173-0447-00), and unit dose packs of 100 tablets (NDC 0173-0447-02). Bottles: Store between 2° and 30°C (36° and 86°F). Dispense in tight container as defined in the USP. Unit Dose Packs: Store between 2° and 30°C (36° and 86°F). ZOFRAN ODT Orally Disintegrating Tablets, 4 mg (as 4 mg ondansetron base) are white, round and plano-convex tablets debossed with a“Z4” on one side in unit dose packs of 30 tablets (NDC 0173- 0569-00). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ZOFRAN ODT Orally Disintegrating Tablets, 8 mg (as 8 mg ondansetron base) are white, round and plano-convex tablets debossed with a “Z8” on one side in unit dose packs of 10 tablets (NDC 0173- 0570-04) and 30 tablets (NDC 0173-0570-00). Store between 2° and 30°C (36° and 86°F). ZOFRAN Oral Solution, a clear, colorless to light yellow liquid with a characteristic strawberry odor, contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron per 5 mL in amber glass bottles of 50 mL with child-resistant closures (NDC 0173-0489-00). Store upright between 15° and 30°C (59° and 86°F). Protect from light. Store bottles upright in cartons. REFERENCES 1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228. 2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649. 3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381. 4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321. 5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557. GlaxoSmithKline Research Triangle Park, NC 27709 ZOFRAN Tablets and Oral Solution: GlaxoSmithKline Research Triangle Park, NC 27709 ZOFRAN ODT Orally Disintegrating Tablets: Manufactured for GlaxoSmithKline Research Triangle Park, NC 27709 by Cardinal Health Blagrove, Swindon, Wiltshire, UK SN5 8RU ©2006, GlaxoSmithKline. All rights reserved. February 2006 RL-2237 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:45.191547	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020103s27,020605s10,020781s10lbl.pdf', 'application_number': 20103, 'submission_type': 'SUPPL ', 'submission_number': 27}
12,218	structural formula PRESCRIBING INFORMATION ZOFRAN® (ondansetron hydrochloride) Tablets ZOFRAN ODT® (ondansetron) Orally Disintegrating Tablets ZOFRAN® (ondansetron hydrochloride) Oral Solution DESCRIPTION The active ingredient in ZOFRAN Tablets and ZOFRAN Oral Solution is ondansetron hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3 [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula: structural formula The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9. Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal saline. The active ingredient in ZOFRAN ODT Orally Disintegrating Tablets is ondansetron base, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H carbazol-4-one. It has the following structural formula: Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The empirical formula is C18H19N3O representing a molecular weight of 293.4. Each 4-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. Each 8-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, pregelatinized starch, hypromellose, magnesium stearate, titanium dioxide, triacetin, and iron oxide yellow (8-mg tablet only). Each 4-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 4 mg ondansetron base. Each 8-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 8 mg ondansetron base. Each ZOFRAN ODT Tablet also contains the inactive ingredients aspartame, gelatin, mannitol, methylparaben sodium, propylparaben sodium, and strawberry flavor. ZOFRAN ODT Tablets are a freeze-dried, orally administered formulation of ondansetron which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. Each 5 mL of ZOFRAN Oral Solution contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. ZOFRAN Oral Solution contains the inactive ingredients citric acid anhydrous, purified water, sodium benzoate, sodium citrate, sorbitol, and strawberry flavor. CLINICAL PHARMACOLOGY Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting reflex. In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT3 receptor antagonist. In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied. Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics: Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%. Ondansetron systemic exposure does not increase proportionately to dose. AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. Bioavailability is also slightly enhanced by the presence of food but unaffected by antacids. Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½ of ondansetron was observed.1 This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended (see PRECAUTIONS: Drug Interactions). In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 1 and 2 taken from 2 studies. Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Pharmacokinetics in Normal Volunteers: Single 8-mg ZOFRAN Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) Systemic Plasma Clearance L/h/kg Absolute Bioavailability 18-40 M F 69.0 62.7 6 5 26.2 42.7 2.0 1.7 3.1 3.5 0.403 0.354 0.483 0.663 61-74 M F 77.5 60.2 6 6 24.1 52.4 2.1 1.9 4.1 4.9 0.384 0.255 0.585 0.643 ≥ 75 M F 78.0 67.6 5 6 37.0 46.1 2.2 2.1 4.5 6.2 0.277 0.249 0.619 0.747 Table 2. Pharmacokinetics in Normal Volunteers: Single 24-mg ZOFRAN Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) 18-43 M F 84.1 71.8 8 8 125.8 194.4 1.9 1.6 4.7 5.8 A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly. In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded. Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron oral mean plasma clearance was reduced by about 50% in patients with severe renal impairment (creatinine clearance < 30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted. Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes. Four- and 8-mg doses of either ZOFRAN Oral Solution or ZOFRAN ODT Orally Disintegrating Tablets are bioequivalent to corresponding doses of ZOFRAN Tablets and may be Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda used interchangeably. One 24-mg ZOFRAN Tablet is bioequivalent to and interchangeable with three 8-mg ZOFRAN Tablets. CLINICAL TRIALS Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 randomized, double-blind, monotherapy trials, a single 24-mg ZOFRAN Tablet was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose ≥ 50 mg/m2 in the historical placebo comparator experienced vomiting in the absence of antiemetic therapy. The first trial compared oral doses of ondansetron 24 mg once a day, 8 mg twice a day, and 32 mg once a day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin ≥ 50 mg/m2. A total of 66% of patients in the ondansetron 24-mg once-a-day group, 55% in the ondansetron 8-mg twice-a-day group, and 55% in the ondansetron 32-mg once-a-day group completed the 24-hour study period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control. In the same trial, 56% of patients receiving oral ondansetron 24 mg once a day experienced no nausea during the 24-hour study period, compared with 36% of patients in the oral ondansetron 8-mg twice-a-day group (P = 0.001) and 50% in the oral ondansetron 32-mg once-a-day group. In a second trial, efficacy of the oral ondansetron 24-mg once-a-day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2, was confirmed. Moderately Emetogenic Chemotherapy: In 1 double-blind US study in 67 patients, ZOFRAN Tablets 8 mg administered twice a day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 3: Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3. Emetic Episodes: Treatment Response Ondansetron 8-mg b.i.d. ZOFRAN Tabletsa Placebo P Value Number of patients 33 34 Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn 20 (61%) 6 (18%) 7 (21%) 2 (6%) 8 (24%) 24 (71%) < 0.001 < 0.001 Median number of emetic episodes 0.0 Undefinedb Median time to first emetic episode (h) Undefinedc 6.5 a The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered twice a day for 2 days after completion of chemotherapy. b Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. c Median undefined since at least 50% of patients did not have any emetic episodes. In 1 double-blind US study in 336 patients, ZOFRAN Tablets 8 mg administered twice a day were as effective as ZOFRAN Tablets 8 mg administered 3 times a day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 4: Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4. Emetic Episodes: Treatment Response Ondansetron 8-mg b.i.d. ZOFRAN Tabletsa 8-mg t.i.d. ZOFRAN Tabletsb Number of patients 165 171 Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn 101 (61%) 16 (10%) 48 (29%) 99 (58%) 17 (10%) 55 (32%) Median number of emetic episodes 0.0 0.0 Median time to first emetic episode (h) Undefinedc Undefinedc Median nausea scores (0-100)d 6 6 a The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered twice a day for 2 days after completion of chemotherapy. b The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered 3 times a day for 2 days after completion of chemotherapy. c Median undefined since at least 50% of patients did not have any emetic episodes. d Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be. Re-treatment: In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ZOFRAN Tablets 8 mg 3 times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the re-treatment courses. Pediatric Studies: Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients 4 to 18 years old with cancer who were given a variety of cisplatin or noncisplatin regimens. In these foreign trials, the initial dose of ZOFRAN® (ondansetron HCl) Injection ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the administration of ZOFRAN Tablets ranging from 4 to 24 mg daily for 3 days. In these studies, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received ZOFRAN Tablets 4 mg 3 times a day to be similar to those in patients 12 to 18 years of age who received ZOFRAN Tablets 8 mg 3 times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, ZOFRAN Tablets were well tolerated in these pediatric patients. Radiation-Induced Nausea and Vomiting: Total Body Irradiation: In a randomized, double-blind study in 20 patients, ZOFRAN Tablets (8 mg given 1.5 hours before each fraction of Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda radiotherapy for 4 days) were significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 2 fractions on day 4. Single High-Dose Fraction Radiotherapy: Ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of ≥ 80 cm2 to the abdomen. Patients received the first dose of ZOFRAN Tablets (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 2 additional doses of study treatment were given (1 tablet late afternoon and 1 tablet before bedtime). If radiotherapy was given in the afternoon, patients took only 1 further tablet that day before bedtime. Patients continued the oral medication on a 3 times a day basis for 3 days. Daily Fractionated Radiotherapy: Ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 135 patients receiving a 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over a field size of ≥ 100 cm2 to the abdomen. Patients received the first dose of ZOFRAN Tablets (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the patient received the first daily radiotherapy fraction, with 2 subsequent doses on a 3 times a day basis. Patients continued the oral medication on a 3 times a day basis on each day of radiotherapy. Postoperative Nausea and Vomiting: Surgical patients who received ondansetron 1 hour before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; and supplemental isoflurane or enflurane) were evaluated in 2 double-blind studies (1 US study, 1 foreign) involving 865 patients. ZOFRAN Tablets (16 mg) were significantly more effective than placebo in preventing postoperative nausea and vomiting. The study populations in all trials thus far consisted of women undergoing inpatient surgical procedures. No studies have been performed in males. No controlled clinical study comparing ZOFRAN Tablets to ZOFRAN Injection has been performed. INDICATIONS AND USAGE 1. Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2. 2. Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. 3. Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen. Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, and ZOFRAN Oral Solution are recommended even where the incidence of postoperative nausea and/or vomiting is low. CONTRAINDICATIONS The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron. ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, and ZOFRAN Oral Solution are contraindicated for patients known to have hypersensitivity to the drug. WARNINGS Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. ECG changes including QT interval prolongation has been seen in patients receiving ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ZOFRAN in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation. PRECAUTIONS General: Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Information for Patients: Phenylketonurics: Phenylketonuric patients should be informed that ZOFRAN ODT Orally Disintegrating Tablets contain phenylalanine (a component of aspartame). Each 4-mg and 8-mg orally disintegrating tablet contains < 0.03 mg phenylalanine. Patients should be instructed not to remove ZOFRAN ODT Tablets from the blister until just prior to dosing. The tablet should not be pushed through the foil. With dry hands, the blister backing should be peeled completely off the blister. The tablet should be gently removed and immediately placed on the tongue to dissolve and be swallowed with the saliva. Peelable illustrated stickers are affixed to the product carton that can be provided with the prescription to ensure proper use and handling of the product. Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450 Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data, no dosage adjustment is recommended for patients on these drugs. Apomorphine: Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, concomitant use of apomorphine with ondansetron is contraindicated (see CONTRAINDICATIONS). Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P-388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. Use in Surgical Patients: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg/day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg/day did not affect fertility or general reproductive performance of male and female rats. Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman. Pediatric Use: Little information is available about dosage in pediatric patients 4 years of age or younger (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION sections for use in pediatric patients 4 to 18 years of age). Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda were subgroup analyses, 938 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL PHARMACOLOGY). ADVERSE REACTIONS The following have been reported as adverse events in clinical trials of patients treated with ondansetron, the active ingredient of ZOFRAN. A causal relationship to therapy with ZOFRAN has been unclear in many cases. Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 5 have been reported in ≥ 5% of adult patients receiving a single 24-mg ZOFRAN Tablet in 2 trials. These patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens (cisplatin dose ≥ 50 mg/m2). Table 5. Principal Adverse Events in US Trials: Single Day Therapy With 24-mg ZOFRAN Tablets (Highly Emetogenic Chemotherapy) Event Ondansetron 24 mg q.d. n = 300 Ondansetron 8 mg b.i.d. n = 124 Ondansetron 32 mg q.d. n = 117 Headache 33 (11%) 16 (13%) 17 (15%) Diarrhea 13 (4%) 9 (7%) 3 (3%) The adverse events in Table 6 have been reported in ≥ 5% of adults receiving either 8 mg of ZOFRAN Tablets 2 or 3 times a day for 3 days or placebo in 4 trials. These patients were receiving concurrent moderately emetogenic chemotherapy, primarily cyclophosphamide-based regimens. Table 6. Principal Adverse Events in US Trials: 3 Days of Therapy With 8-mg ZOFRAN Tablets (Moderately Emetogenic Chemotherapy) Event Ondansetron 8 mg b.i.d. n = 242 Ondansetron 8 mg t.i.d. n = 415 Placebo n = 262 Headache 58 (24%) 113 (27%) 34 (13%) Malaise/fatigue 32 (13%) 37 (9%) 6 (2%) Constipation 22 (9%) 26 (6%) 1 (<1%) Diarrhea 15 (6%) 16 (4%) 10 (4%) Dizziness 13 (5%) 18 (4%) 12 (5%) Central Nervous System: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron. Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hepatic: In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in approximately 1% to 2% of patients receiving ZOFRAN Tablets. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes cannot be clearly determined. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron. Other: Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures have been reported. Except for bronchospasm and anaphylaxis, the relationship to ZOFRAN was unclear. Radiation-Induced Nausea and Vomiting: The adverse events reported in patients receiving ZOFRAN Tablets and concurrent radiotherapy were similar to those reported in patients receiving ZOFRAN Tablets and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea. Postoperative Nausea and Vomiting: The adverse events in Table 7 have been reported in ≥ 5% of patients receiving ZOFRAN Tablets at a dosage of 16 mg orally in clinical trials. With the exception of headache, rates of these events were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications. Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 7. Frequency of Adverse Events From Controlled Studies With ZOFRAN Tablets (Postoperative Nausea and Vomiting) Adverse Event Ondansetron 16 mg (n = 550) Placebo (n = 531) Wound problem 152 (28%) 162 (31%) Drowsiness/sedation 112 (20%) 122 (23%) Headache 49 (9%) 27 (5%) Hypoxia 49 (9%) 35 (7%) Pyrexia 45 (8%) 34 (6%) Dizziness 36 (7%) 34 (6%) Gynecological disorder 36 (7%) 33 (6%) Anxiety/agitation 33 (6%) 29 (5%) Bradycardia 32 (6%) 30 (6%) Shiver(s) 28 (5%) 30 (6%) Urinary retention 28 (5%) 18 (3%) Hypotension 27 (5%) 32 (6%) Pruritus 27 (5%) 20 (4%) Preliminary observations in a small number of subjects suggest a higher incidence of headache when ZOFRAN ODT Orally Disintegrating Tablets are taken with water, when compared to without water. Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of ZOFRAN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ZOFRAN. Cardiovascular: Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron. Hepatobiliary: Liver enzyme abnormalities Lower Respiratory: Hiccups Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions Skin: Urticaria Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Senses: Eye Disorders: Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours. DRUG ABUSE AND DEPENDENCE Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies. OVERDOSAGE There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose. In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in 1 patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of ZOFRAN Tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely. DOSAGE AND ADMINISTRATION Instructions for Use/Handling ZOFRAN ODT Orally Disintegrating Tablets: Do not attempt to push ZOFRAN ODT Tablets through the foil backing. With dry hands, PEEL BACK the foil backing of 1 blister and GENTLY remove the tablet. IMMEDIATELY place the ZOFRAN ODT Tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary. Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy: The recommended adult oral dosage of ZOFRAN is 24 mg given as three 8-mg tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥ 50 mg/m2. Multiday, single-dose administration of a 24 mg dosage has not been studied. Pediatric Use: There is no experience with the use of a 24 mg dosage in pediatric patients. Geriatric Use: The dosage recommendation is the same as for the general population. Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy: The recommended adult oral dosage is one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. Pediatric Use: For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4-mg ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ZOFRAN Oral Solution given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4-mg ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ZOFRAN Oral Solution should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy. Geriatric Use: The dosage is the same as for the general population. Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen: The recommended oral dosage is one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution given 3 times a day. For total body irradiation, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before each fraction of radiotherapy administered each day. For single high-dose fraction radiotherapy to the abdomen, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. For daily fractionated radiotherapy to the abdomen, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given. Pediatric Use: There is no experience with the use of ZOFRAN Tablets, ZOFRAN ODT Tablets, or ZOFRAN Oral Solution in the prevention of radiation-induced nausea and vomiting in pediatric patients. Geriatric Use: The dosage recommendation is the same as for the general population. Postoperative Nausea and Vomiting: The recommended dosage is 16 mg given as two 8-mg ZOFRAN Tablets or two 8-mg ZOFRAN ODT Tablets or 20 mL (4 teaspoonfuls equivalent to 16 mg of ondansetron) of ZOFRAN Oral Solution 1 hour before induction of anesthesia. Pediatric Use: There is no experience with the use of ZOFRAN Tablets, ZOFRAN ODT Tablets, or ZOFRAN Oral Solution in the prevention of postoperative nausea and vomiting in pediatric patients. Geriatric Use: The dosage is the same as for the general population. Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage Adjustment for Patients With Impaired Renal Function: The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron. Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a total daily dose of 8 mg should not be exceeded. HOW SUPPLIED ZOFRAN Tablets, 4 mg (ondansetron HCl dihydrate equivalent to 4 mg of ondansetron), are white, oval, film-coated tablets engraved with "Zofran" on one side and "4" on the other in daily unit dose packs of 3 tablets (NDC 0173-0446-04), bottles of 30 tablets (NDC 0173-0446-00), and unit dose packs of 100 tablets (NDC 0173-0446-02). Bottles: Store between 2° and 30°C (36° and 86°F). Protect from light. Dispense in tight, light-resistant container as defined in the USP. Unit Dose Packs: Store between 2° and 30°C (36° and 86°F). Protect from light. Store blisters in cartons. ZOFRAN Tablets, 8 mg (ondansetron HCl dihydrate equivalent to 8 mg of ondansetron), are yellow, oval, film-coated tablets engraved with "Zofran" on one side and "8" on the other in daily unit dose packs of 3 tablets (NDC 0173-0447-04), bottles of 30 tablets (NDC 0173-0447-00), and unit dose packs of 100 tablets (NDC 0173-0447-02). Bottles: Store between 2° and 30°C (36° and 86°F). Dispense in tight container as defined in the USP. Unit Dose Packs: Store between 2° and 30°C (36° and 86°F). ZOFRAN ODT Orally Disintegrating Tablets, 4 mg (as 4 mg ondansetron base) are white, round and plano-convex tablets debossed with a“Z4” on one side in unit dose packs of 30 tablets (NDC 0173-0569-00). ZOFRAN ODT Orally Disintegrating Tablets, 8 mg (as 8 mg ondansetron base) are white, round and plano-convex tablets debossed with a “Z8” on one side in unit dose packs of 10 tablets (NDC 0173-0570-04) and 30 tablets (NDC 0173-0570-00). Store between 2° and 30°C (36° and 86°F). ZOFRAN Oral Solution, a clear, colorless to light yellow liquid with a characteristic strawberry odor, contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron per 5 mL in amber glass bottles of 50 mL with child-resistant closures (NDC 0173-0489-00). Store upright between 15° and 30°C (59° and 86°F). Protect from light. Store bottles upright in cartons. REFERENCES 1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228. Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649. 3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381. 4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321. 5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557. company logo GlaxoSmithKline Research Triangle Park, NC 27709 ZOFRAN Tablets and Oral Solution: GlaxoSmithKline Research Triangle Park, NC 27709 ZOFRAN ODT Orally Disintegrating Tablets: Manufactured for GlaxoSmithKline Research Triangle Park, NC 27709 by Catalent UK Swindon Zydis Ltd. Blagrove, Swindon, Wiltshire, UK SN5 8RU ©2011, GlaxoSmithKline. All rights reserved. September 2011 ZFT:XPI Reference ID: 3014857 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:45.258508	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020103s030,020605s014,020781s014lbl.pdf', 'application_number': 20103, 'submission_type': 'SUPPL ', 'submission_number': 30}
12,217	PRESCRIBING INFORMATION ZOFRAN® (ondansetron hydrochloride) Tablets ZOFRAN ODT® (ondansetron) Orally Disintegrating Tablets ZOFRAN® (ondansetron hydrochloride) Oral Solution DESCRIPTION The active ingredient in ZOFRAN Tablets and ZOFRAN Oral Solution is ondansetron hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3 [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula: structural formula The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9. Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal saline. The active ingredient in ZOFRAN ODT Orally Disintegrating Tablets is ondansetron base, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H carbazol-4-one. It has the following structural formula: structural formula 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The empirical formula is C18H19N3O representing a molecular weight of 293.4. Each 4-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. Each 8-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, pregelatinized starch, hypromellose, magnesium stearate, titanium dioxide, triacetin, and iron oxide yellow (8-mg tablet only). Each 4-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 4 mg ondansetron base. Each 8-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 8 mg ondansetron base. Each ZOFRAN ODT Tablet also contains the inactive ingredients aspartame, gelatin, mannitol, methylparaben sodium, propylparaben sodium, and strawberry flavor. ZOFRAN ODT Tablets are a freeze-dried, orally administered formulation of ondansetron which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. Each 5 mL of ZOFRAN Oral Solution contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. ZOFRAN Oral Solution contains the inactive ingredients citric acid anhydrous, purified water, sodium benzoate, sodium citrate, sorbitol, and strawberry flavor. CLINICAL PHARMACOLOGY Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting reflex. In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT3 receptor antagonist. In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics: Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%. Ondansetron systemic exposure does not increase proportionately to dose. AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. Bioavailability is also slightly enhanced by the presence of food but unaffected by antacids. Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½ of ondansetron was observed.1 This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended (see PRECAUTIONS: Drug Interactions). In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 1 and 2 taken from 2 studies. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Pharmacokinetics in Normal Volunteers: Single 8-mg ZOFRAN Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) Systemic Plasma Clearance L/h/kg Absolute Bioavailability 18-40 M F 69.0 62.7 6 5 26.2 42.7 2.0 1.7 3.1 3.5 0.403 0.354 0.483 0.663 61-74 M F 77.5 60.2 6 6 24.1 52.4 2.1 1.9 4.1 4.9 0.384 0.255 0.585 0.643 ≥ 75 M F 78.0 67.6 5 6 37.0 46.1 2.2 2.1 4.5 6.2 0.277 0.249 0.619 0.747 Table 2. Pharmacokinetics in Normal Volunteers: Single 24-mg ZOFRAN Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) 18-43 M F 84.1 71.8 8 8 125.8 194.4 1.9 1.6 4.7 5.8 A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly. In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded. Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron oral mean plasma clearance was reduced by about 50% in patients with severe renal impairment (creatinine clearance < 30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted. Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes. Four- and 8-mg doses of either ZOFRAN Oral Solution or ZOFRAN ODT Orally Disintegrating Tablets are bioequivalent to corresponding doses of ZOFRAN Tablets and may be 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda used interchangeably. One 24-mg ZOFRAN Tablet is bioequivalent to and interchangeable with three 8-mg ZOFRAN Tablets. CLINICAL TRIALS Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 randomized, double-blind, monotherapy trials, a single 24-mg ZOFRAN Tablet was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose ≥ 50 mg/m2 in the historical placebo comparator experienced vomiting in the absence of antiemetic therapy. The first trial compared oral doses of ondansetron 24 mg once a day, 8 mg twice a day, and 32 mg once a day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin ≥ 50 mg/m2. A total of 66% of patients in the ondansetron 24-mg once-a-day group, 55% in the ondansetron 8-mg twice-a-day group, and 55% in the ondansetron 32-mg once-a-day group completed the 24-hour study period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control. In the same trial, 56% of patients receiving oral ondansetron 24 mg once a day experienced no nausea during the 24-hour study period, compared with 36% of patients in the oral ondansetron 8-mg twice-a-day group (P = 0.001) and 50% in the oral ondansetron 32-mg once-a-day group. In a second trial, efficacy of the oral ondansetron 24-mg once-a-day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2, was confirmed. Moderately Emetogenic Chemotherapy: In 1 double-blind US study in 67 patients, ZOFRAN Tablets 8 mg administered twice a day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 3: 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3. Emetic Episodes: Treatment Response Ondansetron 8-mg b.i.d. ZOFRAN Tabletsa Placebo P Value Number of patients 33 34 Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn 20 (61%) 6 (18%) 7 (21%) 2 (6%) 8 (24%) 24 (71%) < 0.001 < 0.001 Median number of emetic episodes 0.0 Undefinedb Median time to first emetic episode (h) Undefinedc 6.5 a The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered twice a day for 2 days after completion of chemotherapy. b Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. c Median undefined since at least 50% of patients did not have any emetic episodes. In 1 double-blind US study in 336 patients, ZOFRAN Tablets 8 mg administered twice a day were as effective as ZOFRAN Tablets 8 mg administered 3 times a day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 4: 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4. Emetic Episodes: Treatment Response Ondansetron 8-mg b.i.d. ZOFRAN Tabletsa 8-mg t.i.d. ZOFRAN Tabletsb Number of patients 165 171 Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn 101 (61%) 16 (10%) 48 (29%) 99 (58%) 17 (10%) 55 (32%) Median number of emetic episodes 0.0 0.0 Median time to first emetic episode (h) Undefinedc Undefinedc Median nausea scores (0-100)d 6 6 a The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered twice a day for 2 days after completion of chemotherapy. b The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered 3 times a day for 2 days after completion of chemotherapy. c Median undefined since at least 50% of patients did not have any emetic episodes. d Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be. Re-treatment: In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ZOFRAN Tablets 8 mg 3 times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the re-treatment courses. Pediatric Studies: Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients 4 to 18 years old with cancer who were given a variety of cisplatin or noncisplatin regimens. In these foreign trials, the initial dose of ZOFRAN® (ondansetron HCl) Injection ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the administration of ZOFRAN Tablets ranging from 4 to 24 mg daily for 3 days. In these studies, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received ZOFRAN Tablets 4 mg 3 times a day to be similar to those in patients 12 to 18 years of age who received ZOFRAN Tablets 8 mg 3 times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, ZOFRAN Tablets were well tolerated in these pediatric patients. Radiation-Induced Nausea and Vomiting: Total Body Irradiation: In a randomized, double-blind study in 20 patients, ZOFRAN Tablets (8 mg given 1.5 hours before each fraction of 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda radiotherapy for 4 days) were significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 2 fractions on day 4. Single High-Dose Fraction Radiotherapy: Ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of ≥ 80 cm2 to the abdomen. Patients received the first dose of ZOFRAN Tablets (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 2 additional doses of study treatment were given (1 tablet late afternoon and 1 tablet before bedtime). If radiotherapy was given in the afternoon, patients took only 1 further tablet that day before bedtime. Patients continued the oral medication on a 3 times a day basis for 3 days. Daily Fractionated Radiotherapy: Ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 135 patients receiving a 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over a field size of ≥ 100 cm2 to the abdomen. Patients received the first dose of ZOFRAN Tablets (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the patient received the first daily radiotherapy fraction, with 2 subsequent doses on a 3 times a day basis. Patients continued the oral medication on a 3 times a day basis on each day of radiotherapy. Postoperative Nausea and Vomiting: Surgical patients who received ondansetron 1 hour before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; and supplemental isoflurane or enflurane) were evaluated in 2 double-blind studies (1 US study, 1 foreign) involving 865 patients. ZOFRAN Tablets (16 mg) were significantly more effective than placebo in preventing postoperative nausea and vomiting. The study populations in all trials thus far consisted of women undergoing inpatient surgical procedures. No studies have been performed in males. No controlled clinical study comparing ZOFRAN Tablets to ZOFRAN Injection has been performed. INDICATIONS AND USAGE 1. Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2. 2. Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. 3. Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, and ZOFRAN Oral Solution are recommended even where the incidence of postoperative nausea and/or vomiting is low. CONTRAINDICATIONS The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron. ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, and ZOFRAN Oral Solution are contraindicated for patients known to have hypersensitivity to the drug. WARNINGS Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. PRECAUTIONS General: Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. Information for Patients: Phenylketonurics: Phenylketonuric patients should be informed that ZOFRAN ODT Orally Disintegrating Tablets contain phenylalanine (a component of aspartame). Each 4-mg and 8-mg orally disintegrating tablet contains < 0.03 mg phenylalanine. Patients should be instructed not to remove ZOFRAN ODT Tablets from the blister until just prior to dosing. The tablet should not be pushed through the foil. With dry hands, the blister backing should be peeled completely off the blister. The tablet should be gently removed and immediately placed on the tongue to dissolve and be swallowed with the saliva. Peelable illustrated stickers are affixed to the product carton that can be provided with the prescription to ensure proper use and handling of the product. Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data, no dosage adjustment is recommended for patients on these drugs. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Apomorphine: Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, concomitant use of apomorphine with ondansetron is contraindicated (see CONTRAINDICATIONS). Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P-388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. Use in Surgical Patients: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg/day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg/day did not affect fertility or general reproductive performance of male and female rats. Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman. Pediatric Use: Little information is available about dosage in pediatric patients 4 years of age or younger (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION sections for use in pediatric patients 4 to 18 years of age). Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there were subgroup analyses, 938 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL PHARMACOLOGY). ADVERSE REACTIONS The following have been reported as adverse events in clinical trials of patients treated with ondansetron, the active ingredient of ZOFRAN. A causal relationship to therapy with ZOFRAN has been unclear in many cases. Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 5 have been reported in ≥ 5% of adult patients receiving a single 24-mg ZOFRAN Tablet in 2 trials. These patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens (cisplatin dose ≥ 50 mg/m2). Table 5. Principal Adverse Events in US Trials: Single Day Therapy With 24-mg ZOFRAN Tablets (Highly Emetogenic Chemotherapy) Event Ondansetron 24 mg q.d. n = 300 Ondansetron 8 mg b.i.d. n = 124 Ondansetron 32 mg q.d. n = 117 Headache 33 (11%) 16 (13%) 17 (15%) Diarrhea 13 (4%) 9 (7%) 3 (3%) The adverse events in Table 6 have been reported in ≥ 5% of adults receiving either 8 mg of ZOFRAN Tablets 2 or 3 times a day for 3 days or placebo in 4 trials. These patients were receiving concurrent moderately emetogenic chemotherapy, primarily cyclophosphamide-based regimens. Table 6. Principal Adverse Events in US Trials: 3 Days of Therapy With 8-mg ZOFRAN Tablets (Moderately Emetogenic Chemotherapy) Event Ondansetron 8 mg b.i.d. n = 242 Ondansetron 8 mg t.i.d. n = 415 Placebo n = 262 Headache 58 (24%) 113 (27%) 34 (13%) Malaise/fatigue 32 (13%) 37 (9%) 6 (2%) Constipation 22 (9%) 26 (6%) 1 (<1%) Diarrhea 15 (6%) 16 (4%) 10 (4%) Dizziness 13 (5%) 18 (4%) 12 (5%) Central Nervous System: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron. Hepatic: In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in approximately 1% to 2% of patients receiving ZOFRAN Tablets. The increases were transient and 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes cannot be clearly determined. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron. Other: Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures have been reported. Except for bronchospasm and anaphylaxis, the relationship to ZOFRAN was unclear. Radiation-Induced Nausea and Vomiting: The adverse events reported in patients receiving ZOFRAN Tablets and concurrent radiotherapy were similar to those reported in patients receiving ZOFRAN Tablets and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea. Postoperative Nausea and Vomiting: The adverse events in Table 7 have been reported in ≥ 5% of patients receiving ZOFRAN Tablets at a dosage of 16 mg orally in clinical trials. With the exception of headache, rates of these events were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 7. Frequency of Adverse Events From Controlled Studies With ZOFRAN Tablets (Postoperative Nausea and Vomiting) Adverse Event Ondansetron 16 mg (n = 550) Placebo (n = 531) Wound problem 152 (28%) 162 (31%) Drowsiness/sedation 112 (20%) 122 (23%) Headache 49 (9%) 27 (5%) Hypoxia 49 (9%) 35 (7%) Pyrexia 45 (8%) 34 (6%) Dizziness 36 (7%) 34 (6%) Gynecological disorder 36 (7%) 33 (6%) Anxiety/agitation 33 (6%) 29 (5%) Bradycardia 32 (6%) 30 (6%) Shiver(s) 28 (5%) 30 (6%) Urinary retention 28 (5%) 18 (3%) Hypotension 27 (5%) 32 (6%) Pruritus 27 (5%) 20 (4%) Preliminary observations in a small number of subjects suggest a higher incidence of headache when ZOFRAN ODT Orally Disintegrating Tablets are taken with water, when compared to without water. Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of ZOFRAN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ZOFRAN. Cardiovascular: Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron. Hepatobiliary: Liver enzyme abnormalities Lower Respiratory: Hiccups Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions Skin: Urticaria 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Senses: Eye Disorders: Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours. DRUG ABUSE AND DEPENDENCE Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies. OVERDOSAGE There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose. In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in 1 patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of ZOFRAN Tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely. DOSAGE AND ADMINISTRATION Instructions for Use/Handling ZOFRAN ODT Orally Disintegrating Tablets: Do not attempt to push ZOFRAN ODT Tablets through the foil backing. With dry hands, PEEL BACK the foil backing of 1 blister and GENTLY remove the tablet. IMMEDIATELY place the ZOFRAN ODT Tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary. Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy: The recommended adult oral dosage of ZOFRAN is 24 mg given as three 8-mg tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥ 50 mg/m2. Multiday, single-dose administration of a 24 mg dosage has not been studied. Pediatric Use: There is no experience with the use of a 24 mg dosage in pediatric patients. Geriatric Use: The dosage recommendation is the same as for the general population. Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy: The recommended adult oral dosage is one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. Pediatric Use: For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4-mg ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ZOFRAN Oral Solution given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4-mg ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ZOFRAN Oral Solution should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy. Geriatric Use: The dosage is the same as for the general population. Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen: The recommended oral dosage is one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution given 3 times a day. For total body irradiation, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before each fraction of radiotherapy administered each day. For single high-dose fraction radiotherapy to the abdomen, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. For daily fractionated radiotherapy to the abdomen, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given. Pediatric Use: There is no experience with the use of ZOFRAN Tablets, ZOFRAN ODT Tablets, or ZOFRAN Oral Solution in the prevention of radiation-induced nausea and vomiting in pediatric patients. Geriatric Use: The dosage recommendation is the same as for the general population. Postoperative Nausea and Vomiting: The recommended dosage is 16 mg given as two 8-mg ZOFRAN Tablets or two 8-mg ZOFRAN ODT Tablets or 20 mL (4 teaspoonfuls equivalent to 16 mg of ondansetron) of ZOFRAN Oral Solution 1 hour before induction of anesthesia. Pediatric Use: There is no experience with the use of ZOFRAN Tablets, ZOFRAN ODT Tablets, or ZOFRAN Oral Solution in the prevention of postoperative nausea and vomiting in pediatric patients. Geriatric Use: The dosage is the same as for the general population. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage Adjustment for Patients With Impaired Renal Function: The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron. Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a total daily dose of 8 mg should not be exceeded. HOW SUPPLIED ZOFRAN Tablets, 4 mg (ondansetron HCl dihydrate equivalent to 4 mg of ondansetron), are white, oval, film-coated tablets engraved with "Zofran" on one side and "4" on the other in daily unit dose packs of 3 tablets (NDC 0173-0446-04), bottles of 30 tablets (NDC 0173-0446-00), and unit dose packs of 100 tablets (NDC 0173-0446-02). Bottles: Store between 2° and 30°C (36° and 86°F). Protect from light. Dispense in tight, light-resistant container as defined in the USP. Unit Dose Packs: Store between 2° and 30°C (36° and 86°F). Protect from light. Store blisters in cartons. ZOFRAN Tablets, 8 mg (ondansetron HCl dihydrate equivalent to 8 mg of ondansetron), are yellow, oval, film-coated tablets engraved with "Zofran" on one side and "8" on the other in daily unit dose packs of 3 tablets (NDC 0173-0447-04), bottles of 30 tablets (NDC 0173-0447-00), and unit dose packs of 100 tablets (NDC 0173-0447-02). Bottles: Store between 2° and 30°C (36° and 86°F). Dispense in tight container as defined in the USP. Unit Dose Packs: Store between 2° and 30°C (36° and 86°F). ZOFRAN ODT Orally Disintegrating Tablets, 4 mg (as 4 mg ondansetron base) are white, round and plano-convex tablets debossed with a“Z4” on one side in unit dose packs of 30 tablets (NDC 0173-0569-00). ZOFRAN ODT Orally Disintegrating Tablets, 8 mg (as 8 mg ondansetron base) are white, round and plano-convex tablets debossed with a “Z8” on one side in unit dose packs of 10 tablets (NDC 0173-0570-04) and 30 tablets (NDC 0173-0570-00). Store between 2° and 30°C (36° and 86°F). ZOFRAN Oral Solution, a clear, colorless to light yellow liquid with a characteristic strawberry odor, contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron per 5 mL in amber glass bottles of 50 mL with child-resistant closures (NDC 0173-0489-00). Store upright between 15° and 30°C (59° and 86°F). Protect from light. Store bottles upright in cartons. REFERENCES 1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649. 3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381. 4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321. 5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557. company logo GlaxoSmithKline Research Triangle Park, NC 27709 ZOFRAN Tablets and Oral Solution: GlaxoSmithKline Research Triangle Park, NC 27709 ZOFRAN ODT Orally Disintegrating Tablets: Manufactured for GlaxoSmithKline Research Triangle Park, NC 27709 by Catalent UK Swindon Zydis Ltd. Blagrove, Swindon, Wiltshire, UK SN5 8RU ©2010, GlaxoSmithKline. All rights reserved. May 2010 ZFT:2PI 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:45.263422	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020103s029,020605s013,020781s013lbl.pdf', 'application_number': 20103, 'submission_type': 'SUPPL ', 'submission_number': 29}
12,219	1 2 PRESCRIBING INFORMATION 3 ZOFRAN® 4 (ondansetron hydrochloride) 5 Tablets 6 7 ZOFRAN ODT® 8 (ondansetron) 9 Orally Disintegrating Tablets 10 11 ZOFRAN® 12 (ondansetron hydrochloride) 13 Oral Solution 14 DESCRIPTION 15 The active ingredient in ZOFRAN® Tablets and ZOFRAN® Oral Solution is ondansetron 16 hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and a selective blocking 17 agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3 18 [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has 19 the following structural formula: 20 structural formula 21 22 23 The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9. 24 Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal 25 saline. 26 The active ingredient in ZOFRAN ODT® Orally Disintegrating Tablets is ondansetron base, the 27 racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type. 28 Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H 29 carbazol-4-one. It has the following structural formula: 30 1 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula 31 32 The empirical formula is C18H19N3O representing a molecular weight of 293.4. 33 Each 4-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate 34 equivalent to 4 mg of ondansetron. Each 8-mg ZOFRAN Tablet for oral administration contains 35 ondansetron HCl dihydrate equivalent to 8 mg of ondansetron. Each tablet also contains the 36 inactive ingredients lactose, microcrystalline cellulose, pregelatinized starch, hypromellose, 37 magnesium stearate, titanium dioxide, triacetin, and iron oxide yellow (8-mg tablet only). 38 Each 4-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 4 mg 39 ondansetron base. Each 8-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration 40 contains 8 mg ondansetron base. Each ZOFRAN ODT Tablet also contains the inactive 41 ingredients aspartame, gelatin, mannitol, methylparaben sodium, propylparaben sodium, and 42 strawberry flavor. ZOFRAN ODT Tablets are a freeze-dried, orally administered formulation of 43 ondansetron which rapidly disintegrates on the tongue and does not require water to aid 44 dissolution or swallowing. 45 Each 5 mL of ZOFRAN Oral Solution contains 5 mg of ondansetron HCl dihydrate equivalent 46 to 4 mg of ondansetron. ZOFRAN Oral Solution contains the inactive ingredients citric acid 47 anhydrous, purified water, sodium benzoate, sodium citrate, sorbitol, and strawberry flavor. 48 CLINICAL PHARMACOLOGY 49 Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While its 50 mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor 51 antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve 52 terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain 53 whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites. 54 However, cytotoxic chemotherapy appears to be associated with release of serotonin from the 55 enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic 56 acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The 57 released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the 58 vomiting reflex. 59 In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor 60 of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or 61 pretreatment with a serotonin 5-HT3 receptor antagonist. 62 In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on 63 esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal 64 transit time. Multiday administration of ondansetron has been shown to slow colonic transit in 65 normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. 2 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 66 Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the 67 degree of neuromuscular blockade produced by atracurium. Interactions with general or local 68 anesthetics have not been studied. 69 Pharmacokinetics: Ondansetron is well absorbed from the gastrointestinal tract and undergoes 70 some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of 71 a single 8-mg tablet, is approximately 56%. 72 Ondansetron systemic exposure does not increase proportionately to dose. AUC from a 16-mg 73 tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction 74 of first-pass metabolism at higher oral doses. Bioavailability is also slightly enhanced by the 75 presence of food but unaffected by antacids. 76 Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled 77 dose recovered as the parent compound from the urine. The primary metabolic pathway is 78 hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. 79 Although some nonconjugated metabolites have pharmacologic activity, these are not found in 80 plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. 81 In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic 82 cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall 83 ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of 84 metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one 85 enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little 86 change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by 87 cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained 88 chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½ 89 of ondansetron was observed.1 This resulted in a significant increase in clearance. However, on 90 the basis of available data, no dosage adjustment for ondansetron is recommended (see 91 PRECAUTIONS: Drug Interactions). 92 In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of 93 ondansetron. 94 Gender differences were shown in the disposition of ondansetron given as a single dose. The 95 extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in 96 women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute 97 bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in 98 part be explained by differences in body weight between men and women. It is not known whether 99 these gender-related differences were clinically important. More detailed pharmacokinetic 100 information is contained in Tables 1 and 2 taken from 2 studies. 101 3 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 102 Table 1. Pharmacokinetics in Normal Volunteers: Single 8-mg ZOFRAN Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) Systemic Plasma Clearance L/h/kg Absolute Bioavailability 18-40 M F 69.0 62.7 6 5 26.2 42.7 2.0 1.7 3.1 3.5 0.403 0.354 0.483 0.663 61-74 M F 77.5 60.2 6 6 24.1 52.4 2.1 1.9 4.1 4.9 0.384 0.255 0.585 0.643 ≥ 75 M F 78.0 67.6 5 6 37.0 46.1 2.2 2.1 4.5 6.2 0.277 0.249 0.619 0.747 103 104 Table 2. Pharmacokinetics in Normal Volunteers: Single 24-mg ZOFRAN Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) 18-43 M F 84.1 71.8 8 8 125.8 194.4 1.9 1.6 4.7 5.8 105 106 A reduction in clearance and increase in elimination half-life are seen in patients over 75 years 107 of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 108 65 years of age and those under 65 years of age; there was an insufficient number of patients over 109 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended 110 in the elderly. 111 In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean 112 half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe 113 hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced 2-fold to 3-fold and 114 apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In 115 patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded. 116 Due to the very small contribution (5%) of renal clearance to the overall clearance, renal 117 impairment was not expected to significantly influence the total clearance of ondansetron. 118 However, ondansetron oral mean plasma clearance was reduced by about 50% in patients with 119 severe renal impairment (creatinine clearance < 30 mL/min). This reduction in clearance is 120 variable and was not consistent with an increase in half-life. No reduction in dose or dosing 121 frequency in these patients is warranted. 122 Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the 123 concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes. 124 Four- and 8-mg doses of either ZOFRAN Oral Solution or ZOFRAN ODT Orally 125 Disintegrating Tablets are bioequivalent to corresponding doses of ZOFRAN Tablets and may be 4 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 126 used interchangeably. One 24-mg ZOFRAN Tablet is bioequivalent to and interchangeable with 127 three 8-mg ZOFRAN Tablets. 128 CLINICAL TRIALS 129 Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: 130 In 2 randomized, double-blind, monotherapy trials, a single 24-mg ZOFRAN Tablet was superior 131 to a relevant historical placebo control in the prevention of nausea and vomiting associated with 132 highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2. Steroid administration 133 was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose ≥ 134 50 mg/m2 in the historical placebo comparator experienced vomiting in the absence of antiemetic 135 therapy. 136 The first trial compared oral doses of ondansetron 24 mg once a day, 8 mg twice a day, and 137 32 mg once a day in 357 adult cancer patients receiving chemotherapy regimens containing 138 cisplatin ≥ 50 mg/m2. A total of 66% of patients in the ondansetron 24-mg once-a-day group, 55% 139 in the ondansetron 8-mg twice-a-day group, and 55% in the ondansetron 32-mg once-a-day group 140 completed the 24-hour study period with 0 emetic episodes and no rescue antiemetic medications, 141 the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically 142 significantly superior to a historical placebo control. 143 In the same trial, 56% of patients receiving oral ondansetron 24 mg once a day experienced no 144 nausea during the 24-hour study period, compared with 36% of patients in the oral ondansetron 145 8-mg twice-a-day group (P = 0.001) and 50% in the oral ondansetron 32-mg once-a-day group. 146 In a second trial, efficacy of the oral ondansetron 24-mg once-a-day regimen in the prevention 147 of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including 148 cisplatin ≥ 50 mg/m2, was confirmed. 149 Moderately Emetogenic Chemotherapy: In 1 double-blind US study in 67 patients, 150 ZOFRAN Tablets 8 mg administered twice a day were significantly more effective than placebo 151 in preventing vomiting induced by cyclophosphamide-based chemotherapy containing 152 doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day 153 study period. The results of this study are summarized in Table 3: 154 5 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 155 Table 3. Emetic Episodes: Treatment Response Ondansetron 8-mg b.i.d. ZOFRAN Tabletsa Placebo P Value Number of patients 33 34 Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn 20 (61%) 6 (18%) 7 (21%) 2 (6%) 8 (24%) 24 (71%) < 0.001 < 0.001 Median number of emetic episodes 0.0 Undefinedb Median time to first emetic episode (h) Undefinedc 6.5 156 a The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a 157 subsequent dose 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered twice a 158 day for 2 days after completion of chemotherapy. 159 b Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic 160 episodes. 161 c Median undefined since at least 50% of patients did not have any emetic episodes. 162 163 In 1 double-blind US study in 336 patients, ZOFRAN Tablets 8 mg administered twice a day 164 were as effective as ZOFRAN Tablets 8 mg administered 3 times a day in preventing nausea and 165 vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or 166 doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day 167 study period. The results of this study are summarized in Table 4: 168 6 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 169 Table 4. Emetic Episodes: Treatment Response Ondansetron 8-mg b.i.d. ZOFRAN Tabletsa 8-mg t.i.d. ZOFRAN Tabletsb Number of patients 165 171 Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn 101 (61%) 16 (10%) 48 (29%) 99 (58%) 17 (10%) 55 (32%) Median number of emetic episodes 0.0 0.0 Median time to first emetic episode (h) Undefinedc Undefinedc Median nausea scores (0-100)d 6 6 170 a The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a 171 subsequent dose 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered twice a 172 day for 2 days after completion of chemotherapy. 173 b The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with 174 subsequent doses 4 and 8 hours after the first dose. An 8-mg ZOFRAN Tablet was administered 175 3 times a day for 2 days after completion of chemotherapy. 176 c Median undefined since at least 50% of patients did not have any emetic episodes. 177 d Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be. 178 179 Re-treatment: In uncontrolled trials, 148 patients receiving cyclophosphamide-based 180 chemotherapy were re-treated with ZOFRAN Tablets 8 mg 3 times daily during subsequent 181 chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) 182 of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the 183 re-treatment courses. 184 Pediatric Studies: Three open-label, uncontrolled, foreign trials have been performed with 185 182 pediatric patients 4 to 18 years old with cancer who were given a variety of cisplatin or 186 noncisplatin regimens. In these foreign trials, the initial dose of ZOFRAN® (ondansetron HCl) 187 Injection ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by 188 the administration of ZOFRAN Tablets ranging from 4 to 24 mg daily for 3 days. In these studies, 189 58% of the 170 evaluable patients had a complete response (no emetic episodes) on day 1. Two 190 studies showed the response rates for patients less than 12 years of age who received ZOFRAN 191 Tablets 4 mg 3 times a day to be similar to those in patients 12 to 18 years of age who received 192 ZOFRAN Tablets 8 mg 3 times daily. Thus, prevention of emesis in these pediatric patients was 193 essentially the same as for patients older than 18 years of age. Overall, ZOFRAN Tablets were 194 well tolerated in these pediatric patients. 7 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 195 Radiation-Induced Nausea and Vomiting: Total Body Irradiation: In a randomized, 196 double-blind study in 20 patients, ZOFRAN Tablets (8 mg given 1.5 hours before each fraction of 197 radiotherapy for 4 days) were significantly more effective than placebo in preventing vomiting 198 induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per 199 fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 200 2 fractions on day 4. 201 Single High-Dose Fraction Radiotherapy: Ondansetron was significantly more effective 202 than metoclopramide with respect to complete control of emesis (0 emetic episodes) in a 203 double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over 204 an anterior or posterior field size of ≥ 80 cm2 to the abdomen. Patients received the first dose of 205 ZOFRAN Tablets (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If 206 radiotherapy was given in the morning, 2 additional doses of study treatment were given (1 tablet 207 late afternoon and 1 tablet before bedtime). If radiotherapy was given in the afternoon, patients 208 took only 1 further tablet that day before bedtime. Patients continued the oral medication on a 209 3 times a day basis for 3 days. 210 Daily Fractionated Radiotherapy: Ondansetron was significantly more effective than 211 prochlorperazine with respect to complete control of emesis (0 emetic episodes) in a double-blind 212 trial in 135 patients receiving a 1- to 4-week course of fractionated radiotherapy (180 cGy doses) 213 over a field size of ≥ 100 cm2 to the abdomen. Patients received the first dose of ZOFRAN Tablets 214 (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the patient received the first daily 215 radiotherapy fraction, with 2 subsequent doses on a 3 times a day basis. Patients continued the oral 216 medication on a 3 times a day basis on each day of radiotherapy. 217 Postoperative Nausea and Vomiting: Surgical patients who received ondansetron 1 hour 218 before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or 219 thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular 220 blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; 221 and supplemental isoflurane or enflurane) were evaluated in 2 double-blind studies (1 US study, 222 1 foreign) involving 865 patients. ZOFRAN Tablets (16 mg) were significantly more effective 223 than placebo in preventing postoperative nausea and vomiting. 224 The study populations in all trials thus far consisted of women undergoing inpatient surgical 225 procedures. No studies have been performed in males. No controlled clinical study comparing 226 ZOFRAN Tablets to ZOFRAN Injection has been performed. 227 INDICATIONS AND USAGE 228 1. Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, 229 including cisplatin ≥ 50 mg/m2 . 230 2. Prevention of nausea and vomiting associated with initial and repeat courses of moderately 231 emetogenic cancer chemotherapy. 8 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 232 3. Prevention of nausea and vomiting associated with radiotherapy in patients receiving either 233 total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the 234 abdomen. 235 4. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine 236 prophylaxis is not recommended for patients in whom there is little expectation that nausea 237 and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be 238 avoided postoperatively, ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, 239 and ZOFRAN Oral Solution are recommended even where the incidence of postoperative 240 nausea and/or vomiting is low. 241 CONTRAINDICATIONS 242 The concomitant use of apomorphine with ondansetron is contraindicated based on reports of 243 profound hypotension and loss of consciousness when apomorphine was administered with 244 ondansetron. 245 ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, and ZOFRAN Oral Solution 246 are contraindicated for patients known to have hypersensitivity to the drug. 247 WARNINGS 248 Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity 249 to other selective 5-HT3 receptor antagonists. 250 ECG changes including QT interval prolongation has been seen in patients receiving 251 ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in 252 patients using ondansetron. Avoid ZOFRAN in patients with congenital long QT syndrome. ECG 253 monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or 254 hypomagnesemia), congestive heart failure, bradyarrhythmias or patients taking other medicinal 255 products that lead to QT prolongation. 256 The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists 257 alone. Most reports have been associated with concomitant use of serotonergic drugs (e.g., 258 selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors 259 (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and 260 intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome 261 occurring with overdose of ZOFRAN alone has also been reported. The majority of reports of 262 serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care 263 unit or an infusion center. 264 Symptoms associated with serotonin syndrome may include the following combination of 265 signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), 266 autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, 267 hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, 268 incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, 269 diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with 270 concomitant use of ZOFRAN and other serotonergic drugs. If symptoms of serotonin syndrome 9 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 271 occur, discontinue ZOFRAN and initiate supportive treatment. Patients should be informed of 272 the increased risk of serotonin syndrome, especially if ZOFRAN is used concomitantly with 273 other serotonergic drugs (see PRECAUTIONS and OVERDOSAGE). 274 PRECAUTIONS 275 General: Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not 276 be used instead of nasogastric suction. The use of ondansetron in patients following abdominal 277 surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive 278 ileus and/or gastric distension. 279 Information for Patients: Phenylketonurics: Phenylketonuric patients should be informed 280 that ZOFRAN ODT Orally Disintegrating Tablets contain phenylalanine (a component of 281 aspartame). Each 4-mg and 8-mg orally disintegrating tablet contains < 0.03 mg phenylalanine. 282 Patients should be instructed not to remove ZOFRAN ODT Tablets from the blister until just 283 prior to dosing. The tablet should not be pushed through the foil. With dry hands, the blister 284 backing should be peeled completely off the blister. The tablet should be gently removed and 285 immediately placed on the tongue to dissolve and be swallowed with the saliva. Peelable 286 illustrated stickers are affixed to the product carton that can be provided with the prescription to 287 ensure proper use and handling of the product. 288 Serotonin Syndrome: Advise patients of the possibility of serotonin syndrome with 289 concomitant use of ZOFRAN and another serotonergic agent such as medications to treat 290 depression and migraines. Advise patients to seek immediate medical attention if the following 291 symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with 292 or without gastrointestinal symptoms. 293 Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome 294 P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY, 295 Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450 296 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these 297 enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of 298 available data, no dosage adjustment is recommended for patients on these drugs. 299 Apomorphine: Based on reports of profound hypotension and loss of consciousness when 300 apomorphine was administered with ondansetron, concomitant use of apomorphine with 301 ondansetron is contraindicated (see CONTRAINDICATIONS). 302 Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of 303 CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was 304 significantly increased and ondansetron blood concentrations were decreased. However, on the 305 basis of available data, no dosage adjustment for ondansetron is recommended for patients on 306 these drugs.1,3 307 Serotonergic Drugs: Serotonin syndrome (including altered mental status, autonomic 308 instability, and neuromuscular symptoms) has been described following the concomitant use of 309 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake 10 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 310 inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) (see 311 WARNINGS). 312 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol 313 has been observed, data from 2 small studies indicate that ondansetron may be associated with an 314 increase in patient controlled administration of tramadol.4,5 315 Chemotherapy: Tumor response to chemotherapy in the P-388 mouse leukemia model is not 316 affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the 317 pharmacokinetics of ondansetron. 318 In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of 319 high-dose methotrexate. 320 Use in Surgical Patients: The coadministration of ondansetron had no effect on the 321 pharmacokinetics and pharmacodynamics of temazepam. 322 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not 323 seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg/day, 324 respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral 325 administration of ondansetron up to 15 mg/kg/day did not affect fertility or general reproductive 326 performance of male and female rats. 327 Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been 328 performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively, 329 and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There 330 are, however, no adequate and well-controlled studies in pregnant women. Because animal 331 reproduction studies are not always predictive of human response, this drug should be used during 332 pregnancy only if clearly needed. 333 Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether 334 ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution 335 should be exercised when ondansetron is administered to a nursing woman. 336 Pediatric Use: Little information is available about dosage in pediatric patients 4 years of age or 337 younger (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION 338 sections for use in pediatric patients 4 to 18 years of age). 339 Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and 340 postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there 341 were subgroup analyses, 938 were 65 years of age and over. No overall differences in safety or 342 effectiveness were observed between these subjects and younger subjects, and other reported 343 clinical experience has not identified differences in responses between the elderly and younger 344 patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment 345 is not needed in patients over the age of 65 (see CLINICAL PHARMACOLOGY). 11 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 346 ADVERSE REACTIONS 347 The following have been reported as adverse events in clinical trials of patients treated with 348 ondansetron, the active ingredient of ZOFRAN. A causal relationship to therapy with ZOFRAN 349 has been unclear in many cases. 350 Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 5 have been 351 reported in ≥ 5% of adult patients receiving a single 24-mg ZOFRAN Tablet in 2 trials. These 352 patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens 353 (cisplatin dose ≥ 50 mg/m2). 354 355 Table 5. Principal Adverse Events in US Trials: Single Day Therapy With 24-mg ZOFRAN 356 Tablets (Highly Emetogenic Chemotherapy) Event Ondansetron 24 mg q.d. n = 300 Ondansetron 8 mg b.i.d. n = 124 Ondansetron 32 mg q.d. n = 117 Headache 33 (11%) 16 (13%) 17 (15%) Diarrhea 13 (4%) 9 (7%) 3 (3%) 357 358 The adverse events in Table 6 have been reported in ≥ 5% of adults receiving either 8 mg of 359 ZOFRAN Tablets 2 or 3 times a day for 3 days or placebo in 4 trials. These patients were 360 receiving concurrent moderately emetogenic chemotherapy, primarily cyclophosphamide-based 361 regimens. 362 363 Table 6. Principal Adverse Events in US Trials: 3 Days of Therapy With 8-mg ZOFRAN 364 Tablets (Moderately Emetogenic Chemotherapy) Event Ondansetron 8 mg b.i.d. n = 242 Ondansetron 8 mg t.i.d. n = 415 Placebo n = 262 Headache 58 (24%) 113 (27%) 34 (13%) Malaise/fatigue 32 (13%) 37 (9%) 6 (2%) Constipation 22 (9%) 26 (6%) 1 (<1%) Diarrhea 15 (6%) 16 (4%) 10 (4%) Dizziness 13 (5%) 18 (4%) 12 (5%) 365 366 Central Nervous System: There have been rare reports consistent with, but not diagnostic 367 of, extrapyramidal reactions in patients receiving ondansetron. 368 Hepatic: In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical 369 trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in 370 approximately 1% to 2% of patients receiving ZOFRAN Tablets. The increases were transient and 371 did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient 372 elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did 12 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 373 not occur. The role of cancer chemotherapy in these biochemical changes cannot be clearly 374 determined. 375 There have been reports of liver failure and death in patients with cancer receiving concurrent 376 medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The 377 etiology of the liver failure is unclear. 378 Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron. 379 Other: Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), 380 hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures 381 have been reported. Except for bronchospasm and anaphylaxis, the relationship to ZOFRAN was 382 unclear. 383 Radiation-Induced Nausea and Vomiting: The adverse events reported in patients receiving 384 ZOFRAN Tablets and concurrent radiotherapy were similar to those reported in patients receiving 385 ZOFRAN Tablets and concurrent chemotherapy. The most frequently reported adverse events 386 were headache, constipation, and diarrhea. 387 Postoperative Nausea and Vomiting: The adverse events in Table 7 have been reported in ≥ 388 5% of patients receiving ZOFRAN Tablets at a dosage of 16 mg orally in clinical trials. With the 389 exception of headache, rates of these events were not significantly different in the ondansetron and 390 placebo groups. These patients were receiving multiple concomitant perioperative and 391 postoperative medications. 392 393 Table 7. Frequency of Adverse Events From Controlled Studies With ZOFRAN Tablets 394 (Postoperative Nausea and Vomiting) Adverse Event Ondansetron 16 mg (n = 550) Placebo (n = 531) Wound problem 152 (28%) 162 (31%) Drowsiness/sedation 112 (20%) 122 (23%) Headache 49 (9%) 27 (5%) Hypoxia 49 (9%) 35 (7%) Pyrexia 45 (8%) 34 (6%) Dizziness 36 (7%) 34 (6%) Gynecological disorder 36 (7%) 33 (6%) Anxiety/agitation 33 (6%) 29 (5%) Bradycardia 32 (6%) 30 (6%) Shiver(s) 28 (5%) 30 (6%) Urinary retention 28 (5%) 18 (3%) Hypotension 27 (5%) 32 (6%) Pruritus 27 (5%) 20 (4%) 395 13 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 396 Preliminary observations in a small number of subjects suggest a higher incidence of 397 headache when ZOFRAN ODT Orally Disintegrating Tablets are taken with water, when 398 compared to without water. 399 Observed During Clinical Practice: In addition to adverse events reported from clinical 400 trials, the following events have been identified during post-approval use of oral formulations of 401 ZOFRAN. Because they are reported voluntarily from a population of unknown size, estimates of 402 frequency cannot be made. The events have been chosen for inclusion due to a combination of 403 their seriousness, frequency of reporting, or potential causal connection to ZOFRAN. 404 Cardiovascular: Rarely and predominantly with intravenous ondansetron, transient ECG 405 changes including QT interval prolongation have been reported. 406 General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., 407 anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, shortness of breath, 408 hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and 409 cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable 410 ondansetron. 411 Hepatobiliary: Liver enzyme abnormalities 412 Lower Respiratory: Hiccups 413 Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions 414 Skin: Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis. 415 Special Senses: Eye Disorders: Cases of transient blindness, predominantly during 416 intravenous administration, have been reported. These cases of transient blindness were reported 417 to resolve within a few minutes up to 48 hours. 418 DRUG ABUSE AND DEPENDENCE 419 Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does 420 it substitute for benzodiazepines in direct addiction studies. 421 OVERDOSAGE 422 There is no specific antidote for ondansetron overdose. Patients should be managed with 423 appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily 424 intravenous doses as large as 252 mg have been inadvertently administered without significant 425 adverse events. These doses are more than 10 times the recommended daily dose. 426 In addition to the adverse events listed above, the following events have been described in the 427 setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus 428 severe constipation occurred in 1 patient that was administered 72 mg of ondansetron 429 intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg 430 of ZOFRAN Tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal 431 episode with transient second-degree heart block was observed. In all instances, the events 432 resolved completely. 433 Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral 434 overdoses of ondansetron (exceeding estimated ingestion of 5 mg/kg) in young children. Reported 14 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 435 symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, 436 mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure. 437 Patients required supportive care, including intubation in some cases, with complete recovery 438 without sequelae within 1 to 2 days. 439 DOSAGE AND ADMINISTRATION 440 Instructions for Use/Handling ZOFRAN ODT Orally Disintegrating Tablets: Do not 441 attempt to push ZOFRAN ODT Tablets through the foil backing. With dry hands, PEEL BACK 442 the foil backing of 1 blister and GENTLY remove the tablet. IMMEDIATELY place the 443 ZOFRAN ODT Tablet on top of the tongue where it will dissolve in seconds, then swallow with 444 saliva. Administration with liquid is not necessary. 445 Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer 446 Chemotherapy: The recommended adult oral dosage of ZOFRAN is 24 mg given as three 8-mg 447 tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, 448 including cisplatin ≥ 50 mg/m2. Multiday, single-dose administration of a 24 mg dosage has not 449 been studied. 450 Pediatric Use: There is no experience with the use of a 24 mg dosage in pediatric patients. 451 Geriatric Use: The dosage recommendation is the same as for the general population. 452 Prevention of Nausea and Vomiting Associated With Moderately Emetogenic 453 Cancer Chemotherapy: The recommended adult oral dosage is one 8-mg ZOFRAN Tablet or 454 one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of 455 ZOFRAN Oral Solution given twice a day. The first dose should be administered 30 minutes 456 before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. 457 One 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls 458 equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be administered twice a day 459 (every 12 hours) for 1 to 2 days after completion of chemotherapy. 460 Pediatric Use: For pediatric patients 12 years of age and older, the dosage is the same as for 461 adults. For pediatric patients 4 through 11 years of age, the dosage is one 4-mg ZOFRAN Tablet 462 or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of 463 ZOFRAN Oral Solution given 3 times a day. The first dose should be administered 30 minutes 464 before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first 465 dose. One 4-mg ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful 466 equivalent to 4 mg of ondansetron) of ZOFRAN Oral Solution should be administered 3 times a 467 day (every 8 hours) for 1 to 2 days after completion of chemotherapy. 468 Geriatric Use: The dosage is the same as for the general population. 469 Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total 470 Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen: 471 The recommended oral dosage is one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet 472 or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution given 473 3 times a day. 15 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 474 For total body irradiation, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 475 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution should be 476 administered 1 to 2 hours before each fraction of radiotherapy administered each day. 477 For single high-dose fraction radiotherapy to the abdomen, one 8-mg ZOFRAN Tablet or one 478 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of 479 ZOFRAN Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent 480 doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. 481 For daily fractionated radiotherapy to the abdomen, one 8-mg ZOFRAN Tablet or one 8-mg 482 ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN 483 Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses 484 every 8 hours after the first dose for each day radiotherapy is given. 485 Pediatric Use: There is no experience with the use of ZOFRAN Tablets, ZOFRAN ODT 486 Tablets, or ZOFRAN Oral Solution in the prevention of radiation-induced nausea and vomiting 487 in pediatric patients. 488 Geriatric Use: The dosage recommendation is the same as for the general population. 489 Postoperative Nausea and Vomiting: The recommended dosage is 16 mg given as two 8-mg 490 ZOFRAN Tablets or two 8-mg ZOFRAN ODT Tablets or 20 mL (4 teaspoonfuls equivalent to 491 16 mg of ondansetron) of ZOFRAN Oral Solution 1 hour before induction of anesthesia. 492 Pediatric Use: There is no experience with the use of ZOFRAN Tablets, ZOFRAN ODT 493 Tablets, or ZOFRAN Oral Solution in the prevention of postoperative nausea and vomiting in 494 pediatric patients. 495 Geriatric Use: The dosage is the same as for the general population. 496 Dosage Adjustment for Patients With Impaired Renal Function: The dosage 497 recommendation is the same as for the general population. There is no experience beyond first-day 498 administration of ondansetron. 499 500 Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced and apparent 501 volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a 502 total daily dose of 8 mg should not be exceeded. 503 HOW SUPPLIED 504 ZOFRAN Tablets, 4 mg (ondansetron HCl dihydrate equivalent to 4 mg of ondansetron), are 505 white, oval, film-coated tablets engraved with “Zofran” on one side and “4” on the other in bottles 506 of 30 tablets (NDC 0173-0446-00). 507 Store between 2° and 30°C (36° and 86°F). Protect from light. Dispense in tight, light 508 resistant container as defined in the USP. 509 ZOFRAN Tablets, 8 mg (ondansetron HCl dihydrate equivalent to 8 mg of ondansetron), are 510 yellow, oval, film-coated tablets engraved with “Zofran” on one side and “8” on the other in daily 511 unit dose packs of 3 tablets (NDC 0173-0447-04), and bottles of 30 tablets (NDC 0173-0447-00). 16 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 512 Bottles: Store between 2° and 30°C (36° and 86°F). Dispense in tight container as defined 513 in the USP. 514 Unit Dose Packs: Store between 2° and 30°C (36° and 86°F). 515 ZOFRAN ODT Orally Disintegrating Tablets, 4 mg (as 4 mg ondansetron base) are white, 516 round and plano-convex tablets debossed with a“Z4” on one side in unit dose packs of 30 tablets 517 (NDC 0173-0569-00). 518 ZOFRAN ODT Orally Disintegrating Tablets, 8 mg (as 8 mg ondansetron base) are white, 519 round and plano-convex tablets debossed with a “Z8” on one side in unit dose packs of 30 tablets 520 (NDC 0173-0570-00). 521 Store between 2° and 30°C (36° and 86°F). 522 ZOFRAN Oral Solution, a clear, colorless to light yellow liquid with a characteristic 523 strawberry odor, contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron 524 per 5 mL in amber glass bottles of 50 mL with child-resistant closures (NDC 0173-0489-00). 525 Store upright between 15° and 30°C (59° and 86°F). Protect from light. Store bottles 526 upright in cartons. 527 REFERENCES 528 1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) 529 metabolism in humans. Clin Pharmacol Ther. 1997;61:228. 530 2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 531 oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649. 532 3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral 533 and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381. 534 4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321. 535 5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557. 536 537 538 company logo 539 GlaxoSmithKline 540 Research Triangle Park, NC 27709 541 542 ZOFRAN Tablets and Oral Solution: 543 GlaxoSmithKline 544 Research Triangle Park, NC 27709 545 546 ZOFRAN ODT Orally Disintegrating Tablets: 547 Manufactured for GlaxoSmithKline 548 Research Triangle Park, NC 27709 549 by Catalent UK Swindon Zydis Ltd. 550 Blagrove, Swindon, Wiltshire, UK SN5 8RU 17 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 551 552 ©Year, the GSK group of companies. All rights reserved. 553 554 September 2014 555 ZFT:xPI 18 Reference ID: 3630056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:45.481258	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020103s034,020605s018,020781s018lbl.pdf', 'application_number': 20103, 'submission_type': 'SUPPL ', 'submission_number': 34}
12,220	Xttrium Laboratories, Inc. Confidential Page 24 of 24 Chlorhexidine Gluconate 0.75% Solution Section 1.14.1-Draft Labeling Amendment to NDA 20-111/ -Revision Request Attachment # 1: NDA 20-111 -Revised labeling, 4-ounce Dyna-Hex 0.75% CHG Reference ID: 3305382 (b) (4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Xttrium Laboratories, Inc. Confidential Page 24 of 24 Chlorhexidine Gluconate 0.75% Solution Section 1.14.1-Draft Labeling Amendment to NDA 20-111/ -Revision Request Attachment # 1 (cont’d): NDA 20-111 -Revised labeling, 4-ounce Dyna-Hex 0.75% CHG Reference ID: 3305382 (b) (4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Xttrium Laboratories, Inc. Confidential Page 24 of 24 Chlorhexidine Gluconate 0.75% Solution Section 1.14.1-Draft Labeling Amendment to NDA 20-111/ -Revision Request Attachment # 2: NDA 20-111 -Revised labeling, 8-ounce Dyna-Hex 0.75% CHG Reference ID: 3305382 (b) (4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Xttrium Laboratories, Inc. Confidential Page 24 of 24 Chlorhexidine Gluconate 0.75% Solution Section 1.14.1-Draft Labeling Amendment to NDA 20-111/ -Revision Request Attachment # 2 (cont’d): NDA 20-111 -Revised labeling, 8-ounce Dyna-Hex 0.75% CHG Reference ID: 3305382 (b) (4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Xttrium Laboratories, Inc. Confidential Page 24 of 24 Chlorhexidine Gluconate 0.75% Solution Section 1.14.1-Draft Labeling Amendment to NDA 20-111/ -Revision Request Attachment # 3: NDA 20-111 -Revised labeling, 16-ounce Dyna-Hex 0.75% CHG Reference ID: 3305382 (b) (4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Xttrium Laboratories, Inc. Confidential Page 24 of 24 Chlorhexidine Gluconate 0.75% Solution Section 1.14.1-Draft Labeling Amendment to NDA 20-111/ -Revision Request Attachment # 4: NDA 20-111 -Revised labeling, 30-ounce Dyna-Hex 0.75% CHG Reference ID: 3305382 (b) (4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Xttrium Laboratories, Inc. Confidential Page 24 of 24 Chlorhexidine Gluconate 0.75% Solution Section 1.14.1-Draft Labeling Amendment to NDA 20-111/ -Revision Request Attachment # 5: NDA 20-111 -Revised labeling, 32-ounce Dyna-Hex 0.75% CHG Reference ID: 3305382 (b) (4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Xttrium Laboratories, Inc. Confidential Page 24 of 24 Chlorhexidine Gluconate 0.75% Solution Section 1.14.1-Draft Labeling Amendment to NDA 20-111/ -Revision Request Attachment # 6: NDA 20-111 -Revised labeling, 1-Gallon Dyna-Hex 0.75% CHG Reference ID: 3305382 (b) (4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- JOEL SCHIFFENBAUER 05/08/2013 Reference ID: 3305382 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:45.520327	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020111Orig1s007lbl.pdf', 'application_number': 20111, 'submission_type': 'SUPPL ', 'submission_number': 7}
12,222	1 SUPRANE (desflurane, USP) Rx only Volatile Liquid for Inhalation DESCRIPTION SUPRANE (desflurane, USP), a nonflammable liquid administered via vaporizer, is a general inhalation anesthetic. It is (±)1,2,2,2-tetrafluoroethyl difluoromethyl ether: Some physical constants are: Molecular weight 168.04 Specific gravity (at 20°C/4°C) 1.465 Vapor pressure in mm Hg 669 mm Hg @ 20°C 731 mm Hg @ 22°C 757 mm Hg @ 22.8°C (boiling point;1atm) 764 mm Hg @ 23°C 798 mm Hg @ 24°C 869 mm Hg @ 26°C Partition coefficients at 37°C: Blood/Gas 0.424 Olive Oil/Gas 18.7 Brain/Gas 0.54 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Mean Component/Gas Partition Coefficients: Polypropylene (Y piece) 6.7 Polyethylene (circuit tube) 16.2 Latex rubber (bag) 19.3 Latex rubber (bellows) 10.4 Polyvinylchloride (endotracheal tube) 34.7 Desflurane is nonflammable as defined by the requirements of International Electrotechnical Commission 601-2-13. Desflurane is a colorless, volatile liquid below 22.8°C. Data indicate that desflurane is stable when stored under normal room lighting conditions according to instructions. Desflurane is chemically stable. The only known degradation reaction is through prolonged direct contact with soda lime producing low levels of fluoroform (CHF3). The amount of CHF3 obtained is similar to that produced with MAC-equivalent doses of isoflurane. No discernible degradation occurs in the presence of strong acids. Desflurane does not corrode stainless steel, brass, aluminum, anodized aluminum, nickel plated brass, copper, or beryllium. CLINICAL PHARMACOLOGY SUPRANE (desflurane, USP) is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the SUPRANE absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Minimum alveolar concentration (MAC) of desflurane in oxygen for a 25 year-old adult is 7.3%. The MAC of SUPRANE (desflurane, USP) decreases with increasing age and with addition of depressants such as opioids or benzodiazepines (see DOSAGE AND ADMINISTRATION for details). Pharmacokinetics Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of SUPRANE (desflurane, USP) 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane (See Figure 1). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (See Figure 2). The washout for SUPRANE was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Pharmacodynamics Changes in the clinical effects of SUPRANE (desflurane, USP) rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for SUPRANE are given in the following tables: In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5- 2.0 µg/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N2O 60% in O2 or desflurane/O2 alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, desflurane 2.6-8.4% in N2O 60% in O2, or desflurane 3.1-8.9% in O2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 EMERGENCE AND RECOVERY AFTER OUTPATIENT LAPAROSCOPY 178 FEMALES, AGES 20-47 TIMES IN MINUTES: MEAN ± SD (RANGE) Induction: Propofol Propofol Desflurane/N2O Desflurane/O2 Maintenance: Propofol/N2O Desflurane/N2O Desflurane/N2O Desflurane/O2 Number of Pts: N = 48 N = 44 N = 43 N = 43 —–––– ——— ——— ——— Median age 30 26 29 30 (20 - 43) (21 - 47) (21 - 42) (20 - 40) Anesthetic 49 ± 53 45 ± 35 44 ± 29 41 ± 26 Time (8 - 336) (11 - 178) (14 - 149) (19 - 126) Time to open 7 ± 3 5 ± 2* 5 ± 2* 4 ± 2* eyes (2 - 19) (2 - 10) (2 - 12) (1 - 11) Time to state 9 ± 4 8 ± 3 7 ± 3* 7 ± 3* name (4 - 22) (3 - 18) (3 - 16) (2 - 15) Time to stand 80 ± 34 86 ± 55 81 ± 38 77 ± 38 (40 - 200) (30 - 320) (35 - 190) (35 - 200) Time to walk 110 ± 6 122 ± 85 108 ± 59 108 ± 66 (47 - 285) (37 – 375) (48 - 220) (49 - 250) Time to fit for 152 ± 75 157 ± 80 150 ± 66 155 ± 73 discharge (66 - 375) (73 - 385) (68 - 310) (69 - 325) ———————————————————————————————————— Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the propofol-propofol/N2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or desflurane in O2. Anesthesia was maintained with isoflurane 0.7-1.4% in N2O 60%, desflurane 1.8-7.7% in N2O 60%, or desflurane 4.4-11.9% in O2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 EMERGENCE AND RECOVERY TIMES IN OUTPATIENT SURGERY 46 MALES, 42 FEMALES, AGES 19-70 TIMES IN MINUTES: MEAN ± SD (RANGE) Induction: Thiopental Thiopental Thiopental Desflurane/O2 Maintenance: Isoflurane/N2O Desflurane/N2O Desflurane/O2 Desflurane/O2 Number of Pts: N = 23 N = 21 N = 23 N = 21 ——– ——– —––– ——– Median age 43 40 43 41 (20 - 70) (22 - 67) (19 - 70) (21-64) Anesthetic 49 ± 23 50 ± 19 50 ± 27 51 ± 23 Time (11 - 94) (16 - 80) (16 - 113) (19 - 117) Time to open 13 ± 7 9 ± 3 12 ± 8 8 ± 2* eyes (5 - 33) (4 - 16) (4 - 39) (4 - 13) Time to state 17 ± 10 11 ± 4* 15 ± 10 9 ± 3* name (6 - 44) (6 - 19) (6 - 46) (5 - 14) Time to walk 195 ± 67 176 ± 60 168 ± 34 181 ± 42 (124 - 365) (101 - 315) (119 - 258) (92 - 252) Time to fit for 205 ± 53 202 ± 41 197 ± 35 194 ± 37 discharge (153 - 365) (144 - 315) (155 - 280) (134 - 288) ———————————————————————————————————— Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the thiopental-isoflurane/N2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N2O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of the isoflurane group were able to perform the psychometric tests compared to 76% in the desflurane group (p < 0.05). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 RECOVERY TESTS: PERCENT OF PREOPERATIVE BASELINE VALUES 16 MALES, 22 FEMALES, AGES 20-65 PERCENT: MEAN ± SD 60 minutes After Anesthesia 90 minutes After Anesthesia Maintenance: Desflurane/N2O Isoflurane/N2O Desflurane/N2O Isoflurane/N2O Confusion Δ 66 ± 6 47 ± 8 75 ± 7 56 ± 8 Fatigue Δ 70 ± 9* 33 ± 6 89 ± 12* 47 ± 8 Drowsiness Δ 66 ± 5* 36 ± 8 76 ± 7* 49 ± 9 Clumsiness Δ 65 ± 5 49 ± 8 80 ± 7* 57 ± 9 Comfort Δ 59 ± 7* 30 ± 6 60 ± 8* 31 ± 7 DSST+ score 74 ± 4* 50 ± 9 75 ± 4* 55 ± 7 Trieger Tests++ 67 ± 5 74 ± 6 90 ± 6 83 ± 7 Δ Visual analog scale (values from 0-100; 100 = baseline) + DSST = Digit Symbol Substitution Test ++ Trieger Test = Dot Connecting Test * Differences were statistically significant (p < 0.05) using a two-sample t-test SUPRANE (desflurane, USP) was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO2 38mm Hg) were: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 HEMODYNAMIC EFFECTS OF DESFLURANE DURING CONTROLLED VENTILATION 12 MALE VOLUNTEERS, AGES 16-26 MEAN ± SD (RANGE) Diff Heart Rate (beats/min) Mean Arterial Pressure (mm Hg) Cardiac Index (L/min/m2) Total MAC Equivalent End- Tidal % Des/O2 End- Tidal % Des/N2O O2 N2O O2 N2O O2 N2O ———— ———— ———— — ––– — ––– — — 0 0% / 21% 0% / 0% 69 ± 4 70 ± 6 85 ± 9 85 ± 9 3.7 ± 0.4 3.7 ± 0.4 (63 - 76) (62 - 85) (74 - 102) (74 - 102) (3.0 - 4.2) (3.0 - 4.2) 0.8 6% / 94% 3% / 60% 73 ± 5 77 ± 8 61 ± 5 69 ± 5* 3.2 ± 0.5 3.3 ± 0.5 (67 - 80) (67 - 97) (55 - 70) (62 - 80) (2.6 - 4.0) (2.6 - 4.1) 1.2 9% / 91% 6% / 60% 80 ± 5* 77 ± 7 59 ± 8* 63 ± 8* 3.4 ± 0.5 3.1 ± 0.4* (72 - 84) (67 - 90) (44 - 71) (47 - 74) (2.6 - 4.1) (2.6 - 3.8) 1.7 12% / 88% 9% / 60% 94 ± 14* 79 ± 9 51 ± 12* 59 ± 6* 3.5 ± 0.9 3.0 ± 0.4* (78 - 109) (61 - 91) (31 - 66) (46 - 68) (1.7 - 4.7) (2.4 - 3.6) erences were statistically significant (p < 0.05) compared to awake values, Newman-Keul’s method of multiple comparison. When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation. During spontaneous ventilation in the same volunteers, increasing the concentration of SUPRANE (desflurane, USP) from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N2O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents. The use of desflurane concentrations higher than 1.5 MAC may produce apnea. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 CLINICAL TRIALS SUPRANE (desflurane, USP) was evaluated in 1,843 patients including ambulatory (N=1,061), cardiovascular (N=277), geriatric (N=103), neurosurgical (N=40), and pediatric (N=235) patients. Clinical experience with these patients and with 1,087 control patients in these studies not receiving desflurane are described below. Although desflurane can be used in adults for the inhalation induction of anesthesia via mask, it produces a high incidence of respiratory irritation (coughing, breathholding, apnea, increased secretions, laryngospasm). For incidence, see ADVERSE REACTIONS. Oxyhemoglobin saturation below 90% occurred in 6% of patients (from pooled data, N = 370 adults). Ambulatory Surgery SUPRANE (desflurane, USP) plus N2O was compared to isoflurane plus N2O in multicenter studies (21 sites) of 792 ASA physical status I, II, or III patients aged 18-76 years (median 32). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Induction Anesthetic induction begun with thiopental and continued with desflurane was associated with a 7% incidence of oxyhemoglobin saturation of 90% or less (from pooled data, N = 307) compared with 5% in patients in whom anesthesia was induced with thiopental and isoflurane (from pooled data, N = 152). Maintenance & Recovery SUPRANE (desflurane, USP) with or without N2O or other anesthetics was generally well tolerated. There were no differences between desflurane and the other anesthetics studied in the times that patients were judged fit for discharge. In one outpatient study, patients received a standardized anesthetic consisting of thiopental 4.2-4.4 mg/kg, fentanyl 3.5-4.0 µg/kg, vecuronium 0.05-0.07 mg/kg, and N2O 60% in oxygen with either desflurane 3% or isoflurane 0.6%. Emergence times were significantly different; but times to sit up and discharge were not different (see Table). RECOVERY PROFILES AFTER DESFLURANE 3% IN N2O 60% vs ISOFLURANE 0.6% IN N2O 60% IN OUTPATIENTS 16 MALES, 22 FEMALES, AGES 20-65 MEAN ± SD Isoflurane Desflurane Number 21 17 Anesthetic time (min) 127 ± 80 98 ± 55 Recovery time to: Follow commands (min) 11.1 ± 7.9 6.5 ± 2.3* Sit up (min) 113 ± 27 95 ± 56 Fit for discharge (min) 231 ± 40 207 ± 54 ———————————————————————————————————— Difference was statistically significant from the isoflurane group (p < 0.05), unadjusted for multiple comparisons. Cardiovascular Surgery Desflurane was compared to isoflurane, sufentanil or fentanyl for the anesthetic management of coronary artery bypass graft (CABG), abdominal aortic aneurysm, peripheral vascular and carotid endarterectomy surgery in 7 studies at 15 centers involving a total of 558 patients. In all patients except the desflurane vs sufentanil study, the volatile anesthetics were supplemented with intravenous opioids, usually fentanyl. Blood pressure and heart rate were controlled by changes in concentration of the volatile This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 anesthetics or opioids and cardiovascular drugs if necessary. Oxygen (100%) was the carrier gas in 253 of 277 desflurane cases (24 of 277 received N2O/O2). CARDIOVASCULAR PATIENTS BY AGENT AND TYPE OF SURGERY 418 MALES, 140 FEMALES, AGES 27-87 (MEDIAN 64) 13 Centers 1 Center 1 Center Type of Surgery Isoflurane Desflurane Sufentanil Desflurane Fentanyl Desflurane CABG 58 57 100 100 25 25 Abd Aorta 29 25 - - - - Periph Vasc 24 24 - - - - Carotid Art 45 46 - - - - ____ ____ ____ _____ ____ ____ Total 156 152 100 100 25 25 No differences were found in cardiovascular outcome (death, myocardial infarction, ventricular tachycardia or fibrillation, heart failure) among desflurane and the other anesthetics. Induction Desflurane should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or any patients where increases in heart rate or blood pressure are undesirable. In the desflurane vs sufentanil study, anesthetic induction with desflurane without opioids was associated with new transient ischemia in 14 patients vs 0 in the sufentanil group. In the desflurane group, mean heart rate, arterial pressure, and pulmonary blood pressure increased and stroke volume decreased in contrast to no change in the sufentanil group. Cardiovascular drugs were used frequently in both groups: especially esmolol in the desflurane group (56% vs 0%) and phenylephrine in the sufentanil group (43% vs 27%). When 10 µg/kg of fentanyl was used to supplement induction of anesthesia at one other center, continuous 2-lead ECG analysis showed a low incidence of myocardial ischemia and no difference between desflurane and isoflurane. If desflurane is to be used in patients with coronary artery disease, it should be used in combination with other medications for induction of anesthesia, preferably intravenous opioids and hypnotics. Maintenance & Recovery In studies where desflurane or isoflurane anesthesia was supplemented with fentanyl, there were no differences in hemodynamic variables or the incidence of myocardial This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 ischemia in the patients anesthetized with desflurane compared to those anesthetized with isoflurane. During the precardiopulmonary bypass period, in the desflurane vs sufentanil study where the desflurane patients received no intravenous opioid, more desflurane patients required cardiovascular adjuvants to control hemodynamics than the sufentanil patients. During this period, the incidence of ischemia detected by ECG or echocardiography was not statistically different between desflurane (18 of 99) and sufentanil (9 of 98) groups. However, the duration and severity of ECG-detected myocardial ischemia was significantly less in the desflurane group. The incidence of myocardial ischemia after cardiopulmonary bypass and in the ICU did not differ between groups. Geriatric Surgery SUPRANE (desflurane, USP) plus N2O was compared to isoflurane plus N2O in a multicenter study (6 sites) of 203 ASA physical status II or III elderly patients, aged 57- 91 years (median 71). Induction Most patients were premedicated with fentanyl (mean 2 µg/kg), preoxygenated, and received thiopental (mean 4.3 mg/kg IV) or thiamylal (mean 4 mg/kg IV) followed by succinylcholine (mean 1.4 mg/kg IV) for intubation. Maintenance & Recovery Heart rate and arterial blood pressure remained within 20% of preinduction baseline values during administration of SUPRANE (desflurane, USP) 0.5-7.7% (average 3.6%) with 50-60% N2O. Induction, maintenance, and recovery cardiovascular measurements did not differ from those during isoflurane/N2O administration nor did the postoperative incidence of nausea and vomiting differ. The most common cardiovascular adverse event was hypotension occurring in 8% of the SUPRANE patients and 6% of the isoflurane patients. Neurosurgery SUPRANE (desflurane, USP) was studied in 38 patients aged 26-76 years (median 48 years), ASA physical status II or III undergoing neurosurgical procedures for intracranial lesions. Induction Induction consisted of standard neuroanesthetic techniques including hyperventilation and thiopental. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Maintenance No change in cerebrospinal fluid pressure (CSFP) was observed in 8 patients who had intracranial tumors when the dose of desflurane was 0.5 MAC in N2O 50%. In another study of 9 patients with intracranial tumors, 0.8 MAC desflurane/air/O2 did not increase CSFP above postinduction baseline values. In a different study of 10 patients receiving 1.1 MAC desflurane/air/O2, CSFP increased 7 mm Hg (range 3-13 mm Hg increase, with final values of 11-26 mm Hg) above the predrug values. All volatile anesthetics may increase intracranial pressure in patients with intracranial space occupying lesions. In such patients, desflurane should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) in the period before cranial decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure. The use of a lower dose of desflurane and the administration of a barbiturate and mannitol would be predicted to lessen the effect of desflurane on CSFP. Under hypocapnic conditions (PaCO2 27 mm Hg) desflurane 1 and 1.5 MAC did not increase cerebral blood flow (CBF) in 9 patients undergoing craniotomies. CBF reactivity to increasing PaCO2 from 27 to 35 mm Hg was also maintained at 1.25 MAC desflurane/air/O2. Pediatric Surgery SUPRANE (desflurane, USP) is not recommended for induction of anesthesia in pediatric patients because of the high incidence of moderate to severe upper airway adverse reactions, including laryngospasm, coughing, breathholding, and secretions, seen in studies of induction of anesthesia in pediatric patients. (see WARNINGS and PRECAUTIONS – Pediatric Use). SUPRANE is not approved for maintenance of anesthesia in non-intubated pediatric patients due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions, seen in one study of maintenance of anesthesia in non-intubated pediatric patients. (see WARNINGS and PRECAUTIONS – Pediatric Use). Maintenance & Recovery in Intubated Pediatric Patients SUPRANE (desflurane, USP) is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 SUPRANE, with or without N2O, and halothane, with or without N2O were studied in three clinical trials of pediatric patients aged 2 weeks to 12 years (median 2 years) and ASA physical status I or II. The concentration of SUPRANE (desflurane, USP) required for maintenance of general anesthesia is age-dependent (see INDIVIDUALIZATION OF DOSE). Changes in blood pressure during maintenance of and recovery from anesthesia with desflurane/N2O/O2 are similar to those observed with halothane/N2O/O2. Heart rate during maintenance of anesthesia is approximately 10 beats per minute faster with desflurane than with halothane. Patients were judged fit for discharge from post- anesthesia care units within one hour with both desflurane and halothane. There were no differences in the incidence of nausea and vomiting between patients receiving desflurane or halothane. INDIVIDUALIZATION OF DOSE (Also see DOSAGE AND ADMINISTRATION) Preanesthetic Medication Issues such as whether or not to premedicate and the choice of premedicant(s) must be individualized. In clinical studies, patients scheduled to be anesthetized with desflurane frequently received IV pre-anesthetic medication, such as opioid and/or benzodiazepine. Induction In adults, some premedicated with opioid, a frequent starting concentration was 3% desflurane, increased in 0.5-1.0% increments every 2 to 3 breaths. End-tidal concentrations of 4-11% SUPRANE (desflurane, USP) with and without N2O, produced anesthesia within 2 to 4 minutes. When desflurane was tested as the primary anesthetic induction agent, the incidence of upper airway irritation (apnea, breathholding, laryngospasm, coughing and secretions) was high (see ADVERSE REACTIONS). During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO2 < 90%) was 6%. After induction in adults with an intravenous drug such as thiopental or propofol, desflurane can be started at approximately 0.5-1 MAC, whether the carrier gas is O2 or N2O/O2. Maintenance Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5-8.5% SUPRANE (desflurane, USP) with or without the concomitant use of nitrous oxide. In This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 children, surgical levels of anesthesia may be maintained with concentrations of 5.2-10% SUPRANE with or without the concomitant use of nitrous oxide. During the maintenance of anesthesia, increasing concentrations of SUPRANE (desflurane, USP) produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be due to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of desflurane exceeding 1 MAC may increase heart rate. Thus with this drug, an increased heart rate may not serve reliably as a sign of inadequate anesthesia. SUPRANE (desflurane, USP) decreases the doses of neuromuscular blocking agents required (see PRECAUTIONS, Drug Interactions). INDICATIONS AND USAGE SUPRANE (desflurane, USP) is indicated as an inhalation agent for induction and/or maintenance of anesthesia for inpatient and outpatient surgery in adults (see PRECAUTIONS). SUPRANE (desflurane, USP) is not recommended for induction of anesthesia in pediatric patients because of a high incidence of moderate to severe upper airway adverse events (see WARNINGS). After induction of anesthesia with agents other than SUPRANE, and tracheal intubation, SUPRANE is indicated for maintenance of anesthesia in infants and children. CONTRAINDICATIONS SUPRANE (desflurane, USP) should not be used in patients with a known or suspected genetic susceptibility to malignant hyperthermia. Known sensitivity to SUPRANE (desflurane, USP) or to other halogenated agents. WARNINGS Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. Malignant Hyperthermia In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, desflurane induced malignant hyperthermia. The clinical syndrome is signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia. Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible. Respiratory Adverse Reactions in Pediatric Patients SUPRANE (desflurane, USP) is not recommended for induction of general anesthesia via mask in children due to a high incidence of moderate to severe respiratory adverse reactions seen in clinical studies (see PRECAUTIONS – Pediatric Use). SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions (see PRECAUTIONS – Pediatric Use). Administration of Suprane SUPRANE (desflurane, USP) should be administered only by persons trained in the administration of general anesthesia, using a vaporizer specifically designed and designated for use with desflurane. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Hypotension and respiratory depression increase as anesthesia is deepened. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 PRECAUTIONS During the maintenance of anesthesia, increasing concentrations of SUPRANE (desflurane, USP) produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be related to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of desflurane exceeding 1 MAC may increase heart rate. Thus an increased heart rate may not be a sign of inadequate anesthesia. In patients with intracranial space occupying lesions, SUPRANE (desflurane, USP) should be administered at 0.8 MAC or less, in conjunction with a barbiturate induction and hyperventilation (hypocapnia). Appropriate measures should be taken to maintain cerebral perfusion pressure (see CLINICAL STUDIES, Neurosurgery). In patients with coronary artery disease, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia. Desflurane should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or patients where increases in heart rate or blood pressure are undesirable. It should be used with other medications, preferably intravenous opioids and hypnotics (see CLINICAL STUDIES, Cardiovascular Surgery). Inspired concentrations of SUPRANE (desflurane, USP) greater than 12% have been safely administered to patients, particularly during induction of anesthesia. Such concentrations will proportionately dilute the concentration of oxygen; therefore, maintenance of an adequate concentration of oxygen may require a reduction of nitrous oxide or air if these gases are used concurrently. The recovery from general anesthesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU). SUPRANE (desflurane, USP), like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber cannister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of SUPRANE (desflurane, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 As with other halogenated anesthetic agents, SUPRANE (desflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see CONTRAINDICATIONS). Drug Interactions No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of desflurane on the disposition of other drugs has not been determined. Like isoflurane, desflurane does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine. Benzodiazepines and Opioids (MAC Reduction) Benzodiazepines (midazolam 25-50 µg/kg) decrease the MAC of desflurane by 16% as do the opioids (fentanyl 3-6 µg/kg) by 50% (see DOSAGE AND ADMINISTRATION). Neuromuscular Blocking Agents Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O/opioid anesthesia. The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied. DOSAGE OF MUSCLE RELAXANT CAUSING 95% DEPRESSION IN NEUROMUSCULAR BLOCKADE Mean ED95 (µg/kg) Desflurane Concentration Pancuronium Atracurium Succinylcholine 0.65 MAC 60% N2O/O2 26 123 - 1.25 MAC 60% N2O/O2 18 91 - 1.25 MAC O2 22 120 362 Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of desflurane. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Among nondepolarizing drugs, only pancuronium and atracurium interactions have been studied. In the absence of specific guidelines: 1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine. 2. During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N2O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation. Renal or Hepatic Insufficiency Nine patients receiving SUPRANE (desflurane, USP) (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either SUPRANE (desflurane, USP) (N=28) or isoflurane (N=30) undergoing renal transplant. Eight patients receiving SUPRANE (desflurane, USP) were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal carcinogenicity studies have not been performed with SUPRANE (desflurane, USP). In vitro and in vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by SUPRANE. Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay. Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 Pregnancy Teratogenic Effects No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery. Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. SUPRANE (desflurane, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rats exposed to desflurane at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. Body weight of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation. Labor and Delivery The safety of desflurane during labor or delivery has not been demonstrated. Nursing Mothers The concentrations of desflurane in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, desflurane concentrations in milk are predicted to be below those found with other volatile potent anesthetics. Pediatric Use SUPRANE (desflurane, USP) is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. SUPRANE is not recommended for induction of general anesthesia via mask in children because of the high incidence of moderate to severe respiratory adverse reactions, including laryngospasm (50%), coughing (72%), breathholding (68%), increase in secretions (21%) and oxyhemoglobin desaturation (SpO2 <90%) (26%) seen in clinical studies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions (see below). In a clinical safety trial conducted in children aged 2 to 16 years (mean 7.4 years), following induction with another agent, SUPRANE and isoflurane (in N2O/O2) were compared when delivered via face mask or laryngeal mask airway (LMA) for maintenance of anesthesia, after induction with intravenous propofol or inhaled sevoflurane, in order to assess the relative incidence of respiratory adverse events. MAINTENANCE IN NONINTUBATED PEDIATRIC PATIENTS (FACE MASK OR LMA USED; N=300) All Respiratory Events (>1% of All Pediatric Patients) All Ages (N=300) 2-6 yr (N=150) 7-11 yr (N=81) 12-16 yr (N=69) Any respiratory events 39% 42% 33% 39% Airway obstruction 4% 5% 4% 3% Breath-holding 3% 2% 3% 4% Coughing 26% 33% 19% 22% Laryngospasm 13% 16% 7% 13% Secretion 12% 13% 10% 12% Non-specific desaturation 2% 2% 1% 1% Minor, moderate and severe respiratory events SUPRANE was associated with higher rates (compared with isoflurane) of coughing, laryngospasm and secretions with an overall rate of respiratory events of 39%. Of the pediatric patients exposed to desflurane, 5% experienced severe laryngospasm (associated with significant desaturation; i.e. SpO2 of <90% for >15 seconds, or requiring succinylcholine), across all ages, 2-16 years old. Individual age group incidences of severe laryngospasm were 9% for 2-6 years old, 1% for 7-11 years old, and 1% for 12-16 years old. Removal of LMA under deep anesthesia (MAC range 0.6 – 2.3 with a mean of 1.12 MAC) was associated with a further increase in frequency of respiratory adverse events as compared to awake LMA removal or LMA removal under deep anesthesia with the comparator. The frequency and severity of non-respiratory adverse events were comparable between the two groups. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 The incidence of respiratory events under these conditions was highest in children aged 2-6 years. Therefore, similar studies in children under the age of 2 years were not initiated. Geriatric Use The average MAC for SUPRANE (desflurane, USP) in a 70 year old patient is two-thirds the MAC for a 20 year old patient (see DOSAGE AND ADMINISTRATION). Neurosurgical Use SUPRANE (desflurane, USP) may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. Desflurane should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in CSFP. Appropriate attention must be paid to maintain cerebral perfusion pressure (see CLINICAL STUDIES, Neurosurgery). ADVERSE REACTIONS Adverse event information is derived from controlled clinical trials, the majority of which were conducted in the United States. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered. Of the 2,143 patients exposed to SUPRANE (desflurane, USP) in clinical trials, 370 adults and 152 children were induced with desflurane alone and 987 patients were maintained principally with desflurane. The frequencies given reflect the percent of patients with the event. Each patient was counted once for each type of adverse event. They are presented in alphabetical order according to body system. Frequency of Events Occurring in Greater Than 1% of Clinical Trial Patients (in Reports Deemed “Probably Causally Related”) Induction (use as a mask inhalation agent) ADULT PATIENTS (N=370): Coughing 34%, breathholding 30%, apnea 15%, increased secretions, laryngospasm, oxyhemoglobin desaturation (SpO2 < 90%), pharyngitis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Maintenance or Recovery ADULT AND INTUBATED PEDIATRIC PATIENTS (N=687): Body as a Whole Headache Cardiovascular Bradycardia, hypertension, nodal arrhythmia, tachycardia Digestive Nausea 27%, vomiting 16% Nervous system Increased salivation Respiratory Apnea, breathholding, cough increased, laryngospasm, pharyngitis Special Senses Conjunctivitis (conjunctival hyperemia) * Incidence of events: 3% - 10% Frequency of Events Occurring in Less Than 1% of Patients (in Reports Deemed “Probably Causally Related”) Reported in 3 or more patients, regardless of severity Adverse reactions reported only from postmarketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized. Cardiovascular Arrhythmia, bigeminy, abnormal electrocardiogram, myocardial ischemia, vasodilation Digestive Hepatitis Nervous System Agitation, dizziness. Respiratory Asthma, dyspnea, hypoxia Frequency of Events Occurring in Less Than 1% of Clinical Trial Patients (in Reports Deemed “Causal Relationship Unknown”) Reported in 3 or more patients, regardless of severity Body as a Whole Fever Cardiovascular Hemorrhage, myocardial infarct Metabolic and Nutrition Increased creatinine phosphokinase Musculoskeletal System Myalgia Skin and Appendages Pruritus See WARNINGS for information regarding pediatric use and malignant hyperthermia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 SUPRANE (desflurane, USP) has been associated with perioperative hyperkalemia (see WARNINGS). There have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anesthetic agents, including SUPRANE (desflurane, USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of SUPRANE (desflurane, USP) to these events cannot be established with certainty. Laboratory Findings Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents. DRUG ABUSE AND DEPENDENCE The potential drug abuse liability, and dependence associated with SUPRANE (desflurane, USP) have not been studied. OVERDOSAGE In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of SUPRANE (desflurane, USP), maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. DOSAGE AND ADMINISTRATION Deliver SUPRANE (desflurane, USP) from a vaporizer specifically designed and designated for use with desflurane. The administration of general anesthesia must be individualized based on the patient’s response (see INDIVIDUALIZATION OF DOSE). The following two tables provide mean relative potency based upon age and drug interaction studies in predominately ASA physical status I or II patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 EFFECT OF AGE ON MAC OF DESFLURANE MEAN ± SD (percent atmospheres) Age N O2 100% N N2O 60% 2 weeks 6 9.2 ± 0.0 - - 10 weeks 5 9.4 ± 0.4 - - 9 months 4 10.0 ± 0.7 5 7.5 ± 0.8 2 years 3 9.1 ± 0.6 - - 3 years - - 5 6.4 ± 0.4 4 years 4 8.6 ± 0.6 - - 7 years 5 8.1 ± 0.6 - - 25 years 4 7.3 ± 0.0 4 4.0 ± 0.3 45 years 4 6.0 ± 0.3 6 2.8 ± 0.6 70 years 6 5.2 ± 0.6 6 1.7 ± 0.4 N = number of crossover pairs (using up-and-down method of quantal response) Opioids or benzodiazepines decrease the amounts of SUPRANE (desflurane, USP) required to produce anesthesia. The following table is based on studies of drug interaction (MAC reduction). SUPRANE (desflurane, USP) MAC WITH FENTANYL OR MIDAZOLAM MEAN ± SD (percent reduction) Dose 18-30 years 31-65 years No fentanyl 6.4 ± 0.0 6.3 ± 0.4 3 µg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%) 6 µg/kg fentanyl 3.0 ± 1.2 (53%) 2.3 ± 1.0 (64%) No midazolam 6.9 ± 0.1 5.9 ± 0.6 25 µg/kg midazolam - 4.9 ± 0.9 (16%) 50 µg/kg midazolam - 4.9 ± 0.5 (17%) SUPRANE (desflurane, USP) decreases the doses of neuromuscular blocking agents required (see PRECAUTIONS, Drug Interactions). During the maintenance of anesthesia with inflow rates of 2 L/min or more, the alveolar concentration of desflurane will usually be within 10% of the inspired concentration. (FA/FI, see Figure 1 in Pharmacokinetics section.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 HOW SUPPLIED SUPRANE (desflurane, USP), NDC 10019-641-24, is packaged in amber-colored bottles containing 240 mL desflurane. Safety and Handling Occupational Caution There is no specific work exposure limit established for SUPRANE (desflurane, USP). However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour. The predicted effects of acute overexposure by inhalation of SUPRANE (desflurane, USP) include headache, dizziness or (in extreme cases) unconsciousness. There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. Storage Store at room temperature, 15°-30°C (59°-86°F). SUPRANE (desflurane, USP) has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle cap should be replaced after each use of SUPRANE. Baxter and SUPRANE are trademarks of Baxter International Inc. Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-00070/8.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:45.659128	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020118s012lbl.pdf', 'application_number': 20118, 'submission_type': 'SUPPL ', 'submission_number': 12}
12,221	NDA 20-118/S-010 Page 3 SUPRANE (desflurane, USP) Rx only Volatile Liquid for Inhalation DESCRIPTION SUPRANE (desflurane, USP), a nonflammable liquid administered via vaporizer, is a general inhalation anesthetic. It is (±)1,2,2,2-tetrafluoroethyl difluoromethyl ether: Some physical constants are: Molecular weight 168.04 Specific gravity (at 20°C/4°C) 1.465 Vapor pressure in mm Hg 669 mm Hg @ 20°C 731 mm Hg @ 22°C 757 mm Hg @ 22.8°C (boiling point;1atm) 764 mm Hg @ 23°C 798 mm Hg @ 24°C 869 mm Hg @ 26°C Partition coefficients at 37°C: Blood/Gas 0.424 Olive Oil/Gas 18.7 Brain/Gas 0.54 Mean Component/Gas Partition Coefficients: Polypropylene (Y piece) 6.7 Polyethylene (circuit tube) 16.2 Latex rubber (bag) 19.3 Latex rubber (bellows) 10.4 Polyvinylchloride 34.7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 4 (endotracheal tube) Desflurane is nonflammable as defined by the requirements of International Electrotechnical Commission 601-2-13. Desflurane is a colorless, volatile liquid below 22.8°C. Data indicate that desflurane is stable when stored under normal room lighting conditions according to instructions. Desflurane is chemically stable. The only known degradation reaction is through prolonged direct contact with soda lime producing low levels of fluoroform (CHF3). The amount of CHF3 obtained is similar to that produced with MAC-equivalent doses of isoflurane. No discernible degradation occurs in the presence of strong acids. Desflurane does not corrode stainless steel, brass, aluminum, anodized aluminum, nickel plated brass, copper, or beryllium. CLINICAL PHARMACOLOGY SUPRANE (desflurane, USP) is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the SUPRANE absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Minimum alveolar concentration (MAC) of desflurane in oxygen for a 25 year-old adult is 7.3%. The MAC of SUPRANE (desflurane, USP) decreases with increasing age and with addition of depressants such as opioids or benzodiazepines (see DOSAGE AND ADMINISTRATION for details). Pharmacokinetics Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of SUPRANE (desflurane, USP) 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane (See Figure 1). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (See Figure 2). The washout for SUPRANE was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 5 Pharmacodynamics Changes in the clinical effects of SUPRANE (desflurane, USP) rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for SUPRANE are given in the following tables: In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5-2.0 µg/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N2O 60% in O2 or desflurane/O2 alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, desflurane 2.6-8.4% in N2O 60% in O2, or desflurane 3.1-8.9% in O2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 6 EMERGENCE AND RECOVERY AFTER OUTPATIENT LAPAROSCOPY 178 FEMALES, AGES 20-47 TIMES IN MINUTES: MEAN ± SD (RANGE) Induction: Propofol Propofol Desflurane/N2O Desflurane/O2 Maintenance: Propofol/N2O Desflurane/N2O Desflurane/N2O Desflurane/O2 Number of Pts: N = 48 N = 44 N = 43 N = 43 —–––– ——— ——— ——— Median age 30 26 29 30 (20 - 43) (21 - 47) (21 - 42) (20 - 40) Anesthetic 49 ± 53 45 ± 35 44 ± 29 41 ± 26 Time (8 - 336) (11 - 178) (14 - 149) (19 - 126) Time to open 7 ± 3 5 ± 2* 5 ± 2* 4 ± 2* eyes (2 - 19) (2 - 10) (2 - 12) (1 - 11) Time to state 9 ± 4 8 ± 3 7 ± 3* 7 ± 3* name (4 - 22) (3 - 18) (3 - 16) (2 - 15) Time to stand 80 ± 34 86 ± 55 81 ± 38 77 ± 38 (40 - 200) (30 - 320) (35 - 190) (35 - 200) Time to walk 110 ± 6 122 ± 85 108 ± 59 108 ± 66 (47 - 285) (37 – 375) (48 - 220) (49 - 250) Time to fit for 152 ± 75 157 ± 80 150 ± 66 155 ± 73 discharge (66 - 375) (73 - 385) (68 - 310) (69 - 325) ———————————————————————————————————— Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the propofol-propofol/N2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or desflurane in O2. Anesthesia was maintained with isoflurane 0.7-1.4% in N2O 60%, desflurane 1.8-7.7% in N2O 60%, or desflurane 4.4-11.9% in O2. EMERGENCE AND RECOVERY TIMES IN OUTPATIENT SURGERY 46 MALES, 42 FEMALES, AGES 19-70 TIMES IN MINUTES: MEAN ± SD (RANGE) Induction: Thiopental Thiopental Thiopental Desflurane/O2 Maintenance: Isoflurane/N2O Desflurane/N2O Desflurane/O2 Desflurane/O2 Number of Pts: N = 23 N = 21 N = 23 N = 21 ——– ——– —––– ——– This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 7 Median age 43 40 43 41 (20 - 70) (22 - 67) (19 - 70) (21-64) Anesthetic 49 ± 23 50 ± 19 50 ± 27 51 ± 23 Time (11 - 94) (16 - 80) (16 - 113) (19 - 117) Time to open 13 ± 7 9 ± 3 12 ± 8 8 ± 2* eyes (5 - 33) (4 - 16) (4 - 39) (4 - 13) Time to state 17 ± 10 11 ± 4* 15 ± 10 9 ± 3* name (6 - 44) (6 - 19) (6 - 46) (5 - 14) Time to walk 195 ± 67 176 ± 60 168 ± 34 181 ± 42 (124 - 365) (101 - 315) (119 - 258) (92 - 252) Time to fit for 205 ± 53 202 ± 41 197 ± 35 194 ± 37 discharge (153 - 365) (144 - 315) (155 - 280) (134 - 288) ———————————————————————————————————— Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the thiopental-isoflurane/N2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N2O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of the isoflurane group were able to perform the psychometric tests compared to 76% in the desflurane group (p < 0.05). RECOVERY TESTS: PERCENT OF PREOPERATIVE BASELINE VALUES 16 MALES, 22 FEMALES, AGES 20-65 PERCENT: MEAN ± SD 60 minutes After Anesthesia 90 minutes After Anesthesia Maintenance: Desflurane/N2O Isoflurane/N2O Desflurane/N2O Isoflurane/N2O Confusion ∆ 66 ± 6 47 ± 8 75 ± 7 56 ± 8 Fatigue ∆ 70 ± 9* 33 ± 6 89 ± 12* 47 ± 8 Drowsiness ∆ 66 ± 5* 36 ± 8 76 ± 7* 49 ± 9 Clumsiness ∆ 65 ± 5 49 ± 8 80 ± 7* 57 ± 9 Comfort ∆ 59 ± 7* 30 ± 6 60 ± 8* 31 ± 7 DSST+ score 74 ± 4* 50 ± 9 75 ± 4* 55 ± 7 Trieger Tests++ 67 ± 5 74 ± 6 90 ± 6 83 ± 7 ∆ Visual analog scale (values from 0-100; 100 = baseline) + DSST = Digit Symbol Substitution Test ++ Trieger Test = Dot Connecting Test * Differences were statistically significant (p < 0.05) using a two-sample t-test SUPRANE (desflurane, USP) was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO2 38mm Hg) were: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 8 HEMODYNAMIC EFFECTS OF DESFLURANE DURING CONTROLLED VENTILATION 12 MALE VOLUNTEERS, AGES 16-26 MEAN ± SD (RANGE) Heart Rate (beats/min) Mean Arterial Pressure (mm Hg) Cardiac Index (L/min/m2) Total MAC Equivalent End-Tidal % Des/O2 End-Tidal % Des/N2O O2 N2O O2 N2O O2 N2O ———— ———— ———— — ––– — ––– — — 0 0% / 21% 0% / 0% 69 ± 4 70 ± 6 85 ± 9 85 ± 9 3.7 ± 0.4 3.7 ± 0.4 (63 - 76) (62 - 85) (74 - 102) (74 - 102) (3.0 - 4.2) (3.0 - 4.2) 0.8 6% / 94% 3% / 60% 73 ± 5 77 ± 8 61 ± 5* 69 ± 5* 3.2 ± 0.5 3.3 ± 0.5 (67 - 80) (67 - 97) (55 - 70) (62 - 80) (2.6 - 4.0) (2.6 - 4.1) 1.2 9% / 91% 6% / 60% 80 ± 5* 77 ± 7 59 ± 8* 63 ± 8* 3.4 ± 0.5 3.1 ± 0.4* (72 - 84) (67 - 90) (44 - 71) (47 - 74) (2.6 - 4.1) (2.6 - 3.8) 1.7 12% / 88% 9% / 60% 94 ± 14* 79 ± 9 51 ± 12* 59 ± 6* 3.5 ± 0.9 3.0 ± 0.4* (78 - 109) (61 - 91) (31 - 66) (46 - 68) (1.7 - 4.7) (2.4 - 3.6) Differences were statistically significant (p < 0.05) compared to awake values, Newman-Keul’s method of multiple comparison. When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation. During spontaneous ventilation in the same volunteers, increasing the concentration of SUPRANE (desflurane, USP) from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N2O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents. The use of desflurane concentrations higher than 1.5 MAC may produce apnea. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 9 CLINICAL TRIALS SUPRANE (desflurane, USP) was evaluated in 1,843 patients including ambulatory (N=1,061), cardiovascular (N=277), geriatric (N=103), neurosurgical (N=40), and pediatric (N=235) patients. Clinical experience with these patients and with 1,087 control patients in these studies not receiving desflurane are described below. Although desflurane can be used in adults for the inhalation induction of anesthesia via mask, it produces a high incidence of respiratory irritation (coughing, breathholding, apnea, increased secretions, laryngospasm). For incidence, see ADVERSE REACTIONS. Oxyhemoglobin saturation below 90% occurred in 6% of patients (from pooled data, N = 370 adults). Ambulatory Surgery SUPRANE (desflurane, USP) plus N2O was compared to isoflurane plus N2O in multicenter studies (21 sites) of 792 ASA physical status I, II, or III patients aged 18-76 years (median 32). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 10 Induction Anesthetic induction begun with thiopental and continued with desflurane was associated with a 7% incidence of oxyhemoglobin saturation of 90% or less (from pooled data, N = 307) compared with 5% in patients in whom anesthesia was induced with thiopental and isoflurane (from pooled data, N = 152). Maintenance & Recovery SUPRANE (desflurane, USP) with or without N2O or other anesthetics was generally well tolerated. There were no differences between desflurane and the other anesthetics studied in the times that patients were judged fit for discharge. In one outpatient study, patients received a standardized anesthetic consisting of thiopental 4.2-4.4 mg/kg, fentanyl 3.5-4.0 µg/kg, vecuronium 0.05-0.07 mg/kg, and N2O 60% in oxygen with either desflurane 3% or isoflurane 0.6%. Emergence times were significantly different; but times to sit up and discharge were not different (see Table). RECOVERY PROFILES AFTER DESFLURANE 3% IN N2O 60% vs ISOFLURANE 0.6% IN N2O 60% IN OUTPATIENTS 16 MALES, 22 FEMALES, AGES 20-65 MEAN ± SD Isoflurane Desflurane Number 21 17 Anesthetic time (min) 127 ± 80 98 ± 55 Recovery time to: Follow commands (min) 11.1 ± 7.9 6.5 ± 2.3 Sit up (min) 113 ± 27 95 ± 56 Fit for discharge (min) 231 ± 40 207 ± 54 ———————————————————————————————————— Difference was statistically significant from the isoflurane group (p < 0.05), unadjusted for multiple comparisons. Cardiovascular Surgery Desflurane was compared to isoflurane, sufentanil or fentanyl for the anesthetic management of coronary artery bypass graft (CABG), abdominal aortic aneurysm, peripheral vascular and carotid endarterectomy surgery in 7 studies at 15 centers involving a total of 558 patients. In all patients except the desflurane vs sufentanil study, the volatile anesthetics were supplemented with intravenous opioids, usually fentanyl. Blood pressure and heart rate were controlled by changes in concentration of the volatile This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 11 anesthetics or opioids and cardiovascular drugs if necessary. Oxygen (100%) was the carrier gas in 253 of 277 desflurane cases (24 of 277 received N2O/O2). CARDIOVASCULAR PATIENTS BY AGENT AND TYPE OF SURGERY 418 MALES, 140 FEMALES, AGES 27-87 (MEDIAN 64) 13 Centers 1 Center 1 Center Type of Surgery Isoflurane Desflurane Sufentanil Desflurane Fentanyl Desflurane CABG 58 57 100 100 25 25 Abd Aorta 29 25 - - - - Periph Vasc 24 24 - - - - Carotid Art 45 46 - - - - ____ ____ ____ _____ ____ ____ Total 156 152 100 100 25 25 No differences were found in cardiovascular outcome (death, myocardial infarction, ventricular tachycardia or fibrillation, heart failure) among desflurane and the other anesthetics. Induction Desflurane should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or any patients where increases in heart rate or blood pressure are undesirable. In the desflurane vs sufentanil study, anesthetic induction with desflurane without opioids was associated with new transient ischemia in 14 patients vs 0 in the sufentanil group. In the desflurane group, mean heart rate, arterial pressure, and pulmonary blood pressure increased and stroke volume decreased in contrast to no change in the sufentanil group. Cardiovascular drugs were used frequently in both groups: especially esmolol in the desflurane group (56% vs 0%) and phenylephrine in the sufentanil group (43% vs 27%). When 10 µg/kg of fentanyl was used to supplement induction of anesthesia at one other center, continuous 2-lead ECG analysis showed a low incidence of myocardial ischemia and no difference between desflurane and isoflurane. If desflurane is to be used in patients with coronary artery disease, it should be used in combination with other medications for induction of anesthesia, preferably intravenous opioids and hypnotics. Maintenance & Recovery In studies where desflurane or isoflurane anesthesia was supplemented with fentanyl, there were no differences in hemodynamic variables or the incidence of myocardial ischemia in the patients anesthetized with desflurane compared to those anesthetized with isoflurane. During the precardiopulmonary bypass period, in the desflurane vs sufentanil study where the desflurane patients received no intravenous opioid, more desflurane patients required cardiovascular adjuvants to control hemodynamics than the sufentanil patients. During this period, the incidence of ischemia detected by ECG or echocardiography was not statistically different between desflurane (18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 12 of 99) and sufentanil (9 of 98) groups. However, the duration and severity of ECG-detected myocardial ischemia was significantly less in the desflurane group. The incidence of myocardial ischemia after cardiopulmonary bypass and in the ICU did not differ between groups. Geriatric Surgery SUPRANE (desflurane, USP) plus N2O was compared to isoflurane plus N2O in a multicenter study (6 sites) of 203 ASA physical status II or III elderly patients, aged 57-91 years (median 71). Induction Most patients were premedicated with fentanyl (mean 2 µg/kg), preoxygenated, and received thiopental (mean 4.3 mg/kg IV) or thiamylal (mean 4 mg/kg IV) followed by succinylcholine (mean 1.4 mg/kg IV) for intubation. Maintenance & Recovery Heart rate and arterial blood pressure remained within 20% of preinduction baseline values during administration of SUPRANE (desflurane, USP) 0.5-7.7% (average 3.6%) with 50-60% N2O. Induction, maintenance, and recovery cardiovascular measurements did not differ from those during isoflurane/N2O administration nor did the postoperative incidence of nausea and vomiting differ. The most common cardiovascular adverse event was hypotension occurring in 8% of the SUPRANE patients and 6% of the isoflurane patients. Neurosurgery SUPRANE (desflurane, USP) was studied in 38 patients aged 26-76 years (median 48 years), ASA physical status II or III undergoing neurosurgical procedures for intracranial lesions. Induction Induction consisted of standard neuroanesthetic techniques including hyperventilation and thiopental. Maintenance No change in cerebrospinal fluid pressure (CSFP) was observed in 8 patients who had intracranial tumors when the dose of desflurane was 0.5 MAC in N2O 50%. In another study of 9 patients with intracranial tumors, 0.8 MAC desflurane/air/O2 did not increase CSFP above postinduction baseline values. In a different study of 10 patients receiving 1.1 MAC desflurane/air/O2, CSFP increased 7 mm Hg (range 3-13 mm Hg increase, with final values of 11-26 mm Hg) above the predrug values. All volatile anesthetics may increase intracranial pressure in patients with intracranial space occupying lesions. In such patients, desflurane should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) in the period before cranial This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 13 decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure. The use of a lower dose of desflurane and the administration of a barbiturate and mannitol would be predicted to lessen the effect of desflurane on CSFP. Under hypocapnic conditions (PaCO2 27 mm Hg) desflurane 1 and 1.5 MAC did not increase cerebral blood flow (CBF) in 9 patients undergoing craniotomies. CBF reactivity to increasing PaCO2 from 27 to 35 mm Hg was also maintained at 1.25 MAC desflurane/air/O2. Pediatric Surgery SUPRANE (desflurane, USP) or halothane with or without N2O was used to anesthetize 235 patients aged 2 weeks-12 years (median 2 years), ASA physical status I or II. Induction SUPRANE (desflurane, USP) is not recommended for induction of general anesthesia in infants or pediatric patients because of a high incidence of moderate to severe laryngospasm, coughing, breathholding, and secretions. The occurrence of oxy-hemoglobin desaturation was 26%. For incidence, see ADVERSE REACTIONS. Maintenance & Recovery The concentration of SUPRANE (desflurane, USP) required for maintenance of general anesthesia is age-dependent (see INDIVIDUALIZATION OF DOSE). Changes in blood pressure during maintenance of and recovery from anesthesia with desflurane/N2O/O2 are similar to those observed with halothane/N2O/O2. Heart rate during maintenance of anesthesia is approximately 10 beats per minute faster with desflurane than with halothane. Patients were judged fit for discharge from post- anesthesia care units within one hour with both desflurane and halothane. There were no differences in the incidence of nausea and vomiting between patients receiving desflurane or halothane. INDIVIDUALIZATION OF DOSE (Also see DOSAGE AND ADMINISTRATION) Preanesthetic Medication Issues such as whether or not to premedicate and the choice of premedicant(s) must be individualized. In clinical studies, patients scheduled to be anesthetized with desflurane frequently received IV pre- anesthetic medication, such as opioid and/or benzodiazepine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 14 Induction In adults, some premedicated with opioid, a frequent starting concentration was 3% desflurane, increased in 0.5-1.0% increments every 2 to 3 breaths. End-tidal concentrations of 4-11% SUPRANE (desflurane, USP) with and without N2O, produced anesthesia within 2 to 4 minutes. When desflurane was tested as the primary anesthetic induction agent, the incidence of upper airway irritation (apnea, breathholding, laryngospasm, coughing and secretions) was high (see ADVERSE REACTIONS). During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO2 < 90%) was 6%. After induction in adults with an intravenous drug such as thiopental or propofol, desflurane can be started at approximately 0.5-1 MAC, whether the carrier gas is O2 or N2O/O2. Maintenance Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5-8.5% SUPRANE (desflurane, USP) with or without the concomitant use of nitrous oxide. In children, surgical levels of anesthesia may be maintained with concentrations of 5.2-10% SUPRANE with or without the concomitant use of nitrous oxide. During the maintenance of anesthesia, increasing concentrations of SUPRANE (desflurane, USP) produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be due to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of desflurane exceeding 1 MAC may increase heart rate. Thus with this drug, an increased heart rate may not serve reliably as a sign of inadequate anesthesia. SUPRANE (desflurane, USP) decreases the doses of neuromuscular blocking agents required (see PRECAUTIONS, Drug Interactions). INDICATIONS AND USAGE SUPRANE (desflurane, USP) is indicated as an inhalation agent for induction and/or maintenance of anesthesia for inpatient and outpatient surgery in adults (see PRECAUTIONS). SUPRANE (desflurane, USP) is not recommended for induction of anesthesia in pediatric patients because of a high incidence of moderate to severe upper airway adverse events (see WARNINGS). After induction of anesthesia with agents other than SUPRANE, and tracheal intubation, SUPRANE is indicated for maintenance of anesthesia in infants and children. CONTRAINDICATIONS SUPRANE (desflurane, USP) should not be used in patients with a known or suspected genetic susceptibility to malignant hyperthermia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 15 Known sensitivity to SUPRANE (desflurane, USP) or to other halogenated agents. WARNINGS Pediatric Use SUPRANE (desflurane, USP) is not recommended for induction of general anesthesia via mask in infants or children because of the high incidence of moderate to severe laryngospasm in 50% of patients, coughing 72%, breathholding 68%, increase in secretions 21% and oxyhemoglobin desaturation 26%. SUPRANE (desflurane, USP) should be administered only by persons trained in the administration of general anesthesia, using a vaporizer specifically designed and designated for use with desflurane. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Hypotension and respiratory depression increase as anesthesia is deepened. PRECAUTIONS During the maintenance of anesthesia, increasing concentrations of SUPRANE (desflurane, USP) produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be related to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of desflurane exceeding 1 MAC may increase heart rate. Thus an increased heart rate may not be a sign of inadequate anesthesia. In patients with intracranial space occupying lesions, SUPRANE (desflurane, USP) should be administered at 0.8 MAC or less, in conjunction with a barbiturate induction and hyperventilation (hypocapnia). Appropriate measures should be taken to maintain cerebral perfusion pressure (see CLINICAL STUDIES, Neurosurgery). In patients with coronary artery disease, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia. Desflurane should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or patients where increases in heart rate or blood pressure are undesirable. It should be used with other medications, preferably intravenous opioids and hypnotics (see CLINICAL STUDIES, Cardiovascular Surgery). Inspired concentrations of SUPRANE (desflurane, USP) greater than 12% have been safely administered to patients, particularly during induction of anesthesia. Such concentrations will proportionately dilute the concentration of oxygen; therefore, maintenance of an adequate This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 16 concentration of oxygen may require a reduction of nitrous oxide or air if these gases are used concurrently. The recovery from general anesthesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU). SUPRANE (desflurane, USP), like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber cannister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of SUPRANE (desflurane, USP). As with other halogenated anesthetic agents, SUPRANE (desflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see CONTRAINDICATIONS). Drug Interactions No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of desflurane on the disposition of other drugs has not been determined. Like isoflurane, desflurane does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine. Benzodiazepines and Opioids (MAC Reduction) Benzodiazepines (midazolam 25-50 µg/kg) decrease the MAC of desflurane by 16% as do the opioids (fentanyl 3-6 µg/kg) by 50% (see DOSAGE AND ADMINISTRATION). Neuromuscular Blocking Agents Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O/opioid anesthesia. The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 17 DOSAGE OF MUSCLE RELAXANT CAUSING 95% DEPRESSION IN NEUROMUSCULAR BLOCKADE Mean ED95 (µg/kg) Desflurane Concentration Pancuronium Atracurium Succinylcholine 0.65 MAC 60% N2O/O2 26 123 - 1.25 MAC 60% N2O/O2 18 91 - 1.25 MAC O2 22 120 362 Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of desflurane. Among nondepolarizing drugs, only pancuronium and atracurium interactions have been studied. In the absence of specific guidelines: 1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine. 2. During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N2O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation. Malignant Hyperthermia In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, desflurane induced malignant hyperthermia. The clinical syndrome is signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia. Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible. Renal or Hepatic Insufficiency Nine patients receiving SUPRANE (desflurane, USP) (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 18 hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either SUPRANE (desflurane, USP) (N=28) or isoflurane (N=30) undergoing renal transplant. Eight patients receiving SUPRANE (desflurane, USP) were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal carcinogenicity studies have not been performed with SUPRANE (desflurane, USP). In vitro and in vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by SUPRANE. Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay. Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility. Pregnancy Teratogenic Effects No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery. Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. SUPRANE (desflurane, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rats exposed to desflurane at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. Body weight of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 19 Labor and Delivery The safety of desflurane during labor or delivery has not been demonstrated. Nursing Mothers The concentrations of desflurane in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, desflurane concentrations in milk are predicted to be below those found with other volatile potent anesthetics Pediatric Use SUPRANE (desflurane, USP) is not recommended for induction of general anesthesia via mask in pediatric patients because of the high incidence of moderate to severe laryngospasm, coughing, breathholding and increase in secretions and oxyhemoglobin desaturation (see WARNINGS). Geriatric Use The average MAC for SUPRANE (desflurane, USP) in a 70 year old patient is two-thirds the MAC for a 20 year old patient (see DOSAGE AND ADMINISTRATION). Neurosurgical Use SUPRANE (desflurane, USP) may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. Desflurane should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in CSFP. Appropriate attention must be paid to maintain cerebral perfusion pressure (see CLINICAL STUDIES, Neurosurgery). ADVERSE REACTIONS Adverse event information is derived from controlled clinical trials, the majority of which were conducted in the United States. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered. Of the 1,843 patients exposed to SUPRANE (desflurane, USP) in clinical trials, 370 adults and 152 children were induced with desflurane alone and 687 patients were maintained principally with desflurane. The frequencies given reflect the percent of patients with the event. Each patient was This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 20 counted once for each type of adverse event. They are presented in alphabetical order according to body system. PROBABLY CAUSALLY RELATED: Incidence greater than 1% Induction (use as a mask inhalation agent) ADULT PATIENTS (N=370): Coughing 34%, breathholding 30%, apnea 15%, increased secretions, laryngospasm, oxyhemoglobin desaturation (SpO2 < 90%), pharyngitis. PEDIATRIC PATIENTS (N=152): Coughing 72%, breathholding 68%, laryngospasm 50%, oxyhemoglobin desaturation (SpO2< 90%) 26%, increased secretions 21%, bronchospasm. (See WARNINGS) Maintenance or Recovery ADULT AND PEDIATRIC PATIENTS (N=687): Body as a Whole Headache Cardiovascular Bradycardia, hypertension, nodal arrhythmia, tachycardia Digestive Nausea 27%, vomiting 16% Nervous system Increased Salivation Respiratory Apnea, breathholding, cough increased, laryngospasm, pharyngitis Special Senses Conjunctivitis (conjunctival hyperemia) Incidence of events: 3% - 10% PROBABLY CAUSALLY RELATED: Incidence less than 1% Reported in 3 or more patients, regardless of severity (N=1,843) Adverse reactions reported only from postmarketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized. Cardiovascular Arrhythmia, bigeminy, abnormal electrocardiogram, myocardial ischemia, vasodilation Digestive Hepatitis Nervous System Agitation, dizziness. Respiratory Asthma, dyspnea, hypoxia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 21 CAUSAL RELATIONSHIP UNKNOWN: Incidence less than 1% Reported in 3 or more patients, regardless of severity (N=1,843) Body as a Whole Fever Cardiovascular Hemorrhage, myocardial infarct Metabolic and Nutrition Increased creatinine phosphokinase Musculoskeletal System Myalgia Skin and Appendages Pruritus See PRECAUTIONS for information regarding pediatric use and malignant hyperthermia. Laboratory Findings Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents. DRUG ABUSE AND DEPENDENCE The potential drug abuse liability, and dependence associated with SUPRANE (desflurane, USP) have not been studied. OVERDOSAGE In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of SUPRANE (desflurane, USP), maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. DOSAGE AND ADMINISTRATION Deliver SUPRANE (desflurane, USP) from a vaporizer specifically designed and designated for use with desflurane. The administration of general anesthesia must be individualized based on the patient’s response (see INDIVIDUALIZATION OF DOSE). The following two tables provide mean relative potency based upon age and drug interaction studies in predominately ASA physical status I or II patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 22 EFFECT OF AGE ON MAC OF DESFLURANE MEAN ± SD (percent atmospheres) Age N O2 100% N N2O 60% 2 weeks 6 9.2 ± 0.0 - - 10 weeks 5 9.4 ± 0.4 - - 9 months 4 10.0 ± 0.7 5 7.5 ± 0.8 2 years 3 9.1 ± 0.6 - - 3 years - - 5 6.4 ± 0.4 4 years 4 8.6 ± 0.6 - - 7 years 5 8.1 ± 0.6 - - 25 years 4 7.3 ± 0.0 4 4.0 ± 0.3 45 years 4 6.0 ± 0.3 6 2.8 ± 0.6 70 years 6 5.2 ± 0.6 6 1.7 ± 0.4 N = number of crossover pairs (using up-and-down method of quantal response) Opioids or benzodiazepines decrease the amounts of SUPRANE (desflurane, USP) required to produce anesthesia. The following table is based on studies of drug interaction (MAC reduction). SUPRANE (desflurane, USP) MAC WITH FENTANYL OR MIDAZOLAM MEAN ± SD (percent reduction) Dose 18-30 years 31-65 years No fentanyl 6.4 ± 0.0 6.3 ± 0.4 3 µg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%) 6 µg/kg fentanyl 3.0 ± 1.2 (53%) 2.3 ± 1.0 (64%) No midazolam 6.9 ± 0.1 5.9 ± 0.6 25 µg/kg midazolam - 4.9 ± 0.9 (16%) 50 µg/kg midazolam - 4.9 ± 0.5 (17%) SUPRANE (desflurane, USP) decreases the doses of neuromuscular blocking agents required (see PRECAUTIONS, Drug Interactions). During the maintenance of anesthesia with inflow rates of 2 L/min or more, the alveolar concentration of desflurane will usually be within 10% of the inspired concentration. (FA/FI, see Figure 1 in Pharmacokinetics section.) HOW SUPPLIED SUPRANE (desflurane, USP), NDC 10019-641-24, is packaged in amber-colored bottles containing 240 mL desflurane. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-118/S-010 Page 23 Safety and Handling Occupational Caution There is no specific work exposure limit established for SUPRANE (desflurane, USP). However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour. The predicted effects of acute overexposure by inhalation of SUPRANE (desflurane, USP) include headache, dizziness or (in extreme cases) unconsciousness. There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. Storage Store at room temperature, 15°-30°C (59°-86°F). SUPRANE (desflurane, USP) has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle cap should be replaced after each use of SUPRANE. Baxter and SUPRANE are trademarks of Baxter International Inc. Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA by: Baxter Healthcare Corporation of Puerto Rico Guayama, Puerto Rico 00784 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-00070/5.0 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:45.694858	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020118s010lbl.pdf', 'application_number': 20118, 'submission_type': 'SUPPL ', 'submission_number': 10}
12,223	SUPRANE (desflurane, USP) Rx only Volatile Liquid for Inhalation DESCRIPTION SUPRANE (desflurane, USP), a nonflammable liquid administered via vaporizer, is a general inhalation anesthetic. It is (±)1,2,2,2-tetrafluoroethyl difluoromethyl ether: Some physical constants are: Molecular weight Specific gravity (at 20°C/4°C) Vapor pressure in mm Hg 168.04 1.465 669 mm Hg @ 20°C 731 mm Hg @ 22°C 757 mm Hg @ 22.8°C (boiling point;1atm) 764 mm Hg @ 23°C 798 mm Hg @ 24°C 869 mm Hg @ 26°C Partition coefficients at 37°C: Blood/Gas Olive Oil/Gas Brain/Gas 0.424 18.7 0.54 1 Mean Component/Gas Partition Coefficients: Polypropylene (Y piece) 6.7 Polyethylene (circuit tube) 16.2 Latex rubber (bag) 19.3 Latex rubber (bellows) 10.4 Polyvinylchloride 34.7 (endotracheal tube) Desflurane is nonflammable as defined by the requirements of International Electrotechnical Commission 601-2-13. Desflurane is a colorless, volatile liquid below 22.8°C. Data indicate that desflurane is stable when stored under normal room lighting conditions according to instructions. Desflurane is chemically stable. The only known degradation reaction is through prolonged direct contact with soda lime producing low levels of fluoroform (CHF3). The amount of CHF3 obtained is similar to that produced with MAC-equivalent doses of isoflurane. No discernible degradation occurs in the presence of strong acids. Desflurane does not corrode stainless steel, brass, aluminum, anodized aluminum, nickel plated brass, copper, or beryllium. CLINICAL PHARMACOLOGY SUPRANE (desflurane, USP) is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the SUPRANE absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Minimum alveolar concentration (MAC) of desflurane in oxygen for a 25 year-old adult is 7.3%. The MAC of SUPRANE (desflurane, USP) decreases with increasing age and with addition of depressants such as opioids or benzodiazepines (see DOSAGE AND ADMINISTRATION for details). Pharmacokinetics Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of SUPRANE (desflurane, USP) 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were 2 measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane (See Figure 1). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (See Figure 2). The washout for SUPRANE was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane. Graph 3 Graph Pharmacodynamics Changes in the clinical effects of SUPRANE (desflurane, USP) rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for SUPRANE are given in the following tables: In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5 2.0 µg/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N2O 60% in O2 or desflurane/O2 alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, desflurane 2.6-8.4% in N2O 60% in O2, or desflurane 3.1-8.9% in O2. 4 EMERGENCE AND RECOVERY AFTER OUTPATIENT LAPAROSCOPY 178 FEMALES, AGES 20-47 TIMES IN MINUTES: MEAN ± SD (RANGE) Induction: Propofol Propofol Desflurane/N2O Desflurane/O2 Maintenance: Propofol/N2O Desflurane/N2O Desflurane/N2O Desflurane/O2 Number of Pts: N = 48 N = 44 N = 43 N = 43 —–––– ——— ——— ——— Median age 30 26 29 30 (20 - 43) (21 - 47) (21 - 42) (20 - 40) Anesthetic 49 ± 53 45 ± 35 44 ± 29 41 ± 26 Time (8 - 336) (11 - 178) (14 - 149) (19 - 126) Time to open 7 ± 3 5 ± 2* 5 ± 2* 4 ± 2* eyes (2 - 19) (2 - 10) (2 - 12) (1 - 11) Time to state 9 ± 4 8 ± 3 7 ± 3* 7 ± 3* name (4 - 22) (3 - 18) (3 - 16) (2 - 15) Time to stand 80 ± 34 86 ± 55 81 ± 38 77 ± 38 (40 - 200) (30 - 320) (35 - 190) (35 - 200) Time to walk 110 ± 6 122 ± 85 108 ± 59 108 ± 66 (47 - 285) (37 – 375) (48 - 220) (49 - 250) Time to fit for 152 ± 75 157 ± 80 150 ± 66 155 ± 73 discharge (66 - 375) (73 - 385) (68 - 310) (69 - 325) ———————————————————————————————————— Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the propofol-propofol/N2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or desflurane in O2. Anesthesia was maintained with isoflurane 0.7-1.4% in N2O 60%, desflurane 1.8-7.7% in N2O 60%, or desflurane 4.4-11.9% in O2. 5 EMERGENCE AND RECOVERY TIMES IN OUTPATIENT SURGERY 46 MALES, 42 FEMALES, AGES 19-70 TIMES IN MINUTES: MEAN ± SD (RANGE) Induction: Thiopental Thiopental Thiopental Desflurane/O2 Maintenance: Isoflurane/N2O Desflurane/N2O Desflurane/O2 Desflurane/O2 Number of Pts: N = 23 N = 21 N = 23 N = 21 ——– ——– —––– ——– Median age 43 40 43 41 (20 - 70) (22 - 67) (19 - 70) (21-64) Anesthetic 49 ± 23 50 ± 19 50 ± 27 51 ± 23 Time (11 - 94) (16 - 80) (16 - 113) (19 - 117) Time to open 13 ± 7 9 ± 3 12 ± 8 8 ± 2* eyes (5 - 33) (4 - 16) (4 - 39) (4 - 13) Time to state 17 ± 10 11 ± 4* 15 ± 10 9 ± 3* name (6 - 44) (6 - 19) (6 - 46) (5 - 14) Time to walk 195 ± 67 176 ± 60 168 ± 34 181 ± 42 (124 - 365) (101 - 315) (119 - 258) (92 - 252) Time to fit for 205 ± 53 202 ± 41 197 ± 35 194 ± 37 discharge (153 - 365) (144 - 315) (155 - 280) (134 - 288) ———————————————————————————————————— Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the thiopental-isoflurane/N2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N2O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of the isoflurane group were able to perform the psychometric tests compared to 76% in the desflurane group (p < 0.05). 6 RECOVERY TESTS: PERCENT OF PREOPERATIVE BASELINE VALUES 16 MALES, 22 FEMALES, AGES 20-65 PERCENT: MEAN ± SD 60 minutes After Anesthesia 90 minutes After Anesthesia Maintenance: Desflurane/N2O Isoflurane/N2O Desflurane/N2O Isoflurane/N2O Confusion Δ 66 ± 6 47 ± 8 75 ± 7 56 ± 8 Fatigue Δ 70 ± 9* 33 ± 6 89 ± 12* 47 ± 8 Drowsiness Δ 66 ± 5* 36 ± 8 76 ± 7* 49 ± 9 Clumsiness Δ 65 ± 5 49 ± 8 80 ± 7* 57 ± 9 Comfort Δ 59 ± 7* 30 ± 6 60 ± 8* 31 ± 7 DSST+ score 74 ± 4* 50 ± 9 75 ± 4* 55 ± 7 Trieger Tests++ 67 ± 5 74 ± 6 90 ± 6 83 ± 7 Δ Visual analog scale (values from 0-100; 100 = baseline) + DSST = Digit Symbol Substitution Test ++ Trieger Test = Dot Connecting Test * Differences were statistically significant (p < 0.05) using a two-sample t-test SUPRANE (desflurane, USP) was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO2 38 mm Hg) were: 7 HEMODYNAMIC EFFECTS OF DESFLURANE DURING CONTROLLED VENTILATION 12 MALE VOLUNTEERS, AGES 16-26 MEAN ± SD (RANGE) Mean Arterial Heart Rate Cardiac Index Pressure (beats/min) (L/min/m2) (mm Hg) End- End- Total MAC Tidal % Tidal % Equivalent Des/O2 Des/N2O O2 N2O O2 N2O O2 N2O ———— ———— ———— — ––– — ––– — — 0 0% / 21% 0% / 0% 69 ± 4 70 ± 6 85 ± 9 85 ± 9 3.7 ± 0.4 3.7 ± 0.4 (63 - 76) (62 - 85) (74 - 102) (74 - 102) (3.0 - 4.2) (3.0 - 4.2) 0.8 6% / 94% 3% / 60% 73 ± 5 77 ± 8 61 ± 5* 69 ± 5* 3.2 ± 0.5 3.3 ± 0.5 (67 - 80) (67 - 97) (55 - 70) (62 - 80) (2.6 - 4.0) (2.6 - 4.1) 1.2 9% / 91% 6% / 60% 80 ± 5* 77 ± 7 59 ± 8* 63 ± 8* 3.4 ± 0.5 3.1 ± 0.4* (72 - 84) (67 - 90) (44 - 71) (47 - 74) (2.6 - 4.1) (2.6 - 3.8) 1.7 12% / 88% 9% / 60% 94 ± 14* 79 ± 9 51 ± 12* 59 ± 6* 3.5 ± 0.9 3.0 ± 0.4* (78 - 109) (61 - 91) (31 - 66) (46 - 68) (1.7 - 4.7) (2.4 - 3.6) Differences were statistically significant (p < 0.05) compared to awake values, Newman-Keul’s method of multiple comparison. When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation. During spontaneous ventilation in the same volunteers, increasing the concentration of SUPRANE (desflurane, USP) from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N2O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents. The use of desflurane concentrations higher than 1.5 MAC may produce apnea. 8 Graph CLINICAL TRIALS SUPRANE (desflurane, USP) was evaluated in 1,843 patients including ambulatory (N=1,061), cardiovascular (N=277), geriatric (N=103), neurosurgical (N=40), and pediatric (N=235) patients. Clinical experience with these patients and with 1,087 control patients in these studies not receiving desflurane are described below. Although desflurane can be used in adults for the inhalation induction of anesthesia via mask, it produces a high incidence of respiratory irritation (coughing, breathholding, apnea, increased secretions, laryngospasm). For incidence, see ADVERSE REACTIONS. Oxyhemoglobin saturation below 90% occurred in 6% of patients (from pooled data, N = 370 adults). Ambulatory Surgery SUPRANE (desflurane, USP) plus N2O was compared to isoflurane plus N2O in multicenter studies (21 sites) of 792 ASA physical status I, II, or III patients aged 18-76 years (median 32). 9 Induction Anesthetic induction begun with thiopental and continued with desflurane was associated with a 7% incidence of oxyhemoglobin saturation of 90% or less (from pooled data, N = 307) compared with 5% in patients in whom anesthesia was induced with thiopental and isoflurane (from pooled data, N = 152). Maintenance & Recovery SUPRANE (desflurane, USP) with or without N2O or other anesthetics was generally well tolerated. There were no differences between desflurane and the other anesthetics studied in the times that patients were judged fit for discharge. In one outpatient study, patients received a standardized anesthetic consisting of thiopental 4.2-4.4 mg/kg, fentanyl 3.5-4.0 µg/kg, vecuronium 0.05-0.07 mg/kg, and N2O 60% in oxygen with either desflurane 3% or isoflurane 0.6%. Emergence times were significantly different; but times to sit up and discharge were not different (see Table). RECOVERY PROFILES AFTER DESFLURANE 3% IN N2O 60% vs ISOFLURANE 0.6% IN N2O 60% IN OUTPATIENTS 16 MALES, 22 FEMALES, AGES 20-65 MEAN ± SD Isoflurane Desflurane Number 21 17 Anesthetic time (min) 127 ± 80 98 ± 55 Recovery time to: Follow commands 11.1 ± 7.9 6.5 ± 2.3 (min) Sit up (min) 113 ± 27 95 ± 56 Fit for discharge (min) 231 ± 40 207 ± 54 ———————————————————————————————————— Difference was statistically significant from the isoflurane group (p < 0.05), unadjusted for multiple comparisons. Cardiovascular Surgery Desflurane was compared to isoflurane, sufentanil or fentanyl for the anesthetic management of coronary artery bypass graft (CABG), abdominal aortic aneurysm, peripheral vascular and carotid endarterectomy surgery in 7 studies at 15 centers involving a total of 558 patients. In all patients except the desflurane vs sufentanil study, the volatile anesthetics were supplemented with intravenous opioids, usually fentanyl. Blood pressure and heart rate were controlled by changes in concentration of the volatile 10 ____ ____ ____ _____ ____ ____ anesthetics or opioids and cardiovascular drugs if necessary. Oxygen (100%) was the carrier gas in 253 of 277 desflurane cases (24 of 277 received N2O/O2). CARDIOVASCULAR PATIENTS BY AGENT AND TYPE OF SURGERY 418 MALES, 140 FEMALES, AGES 27-87 (MEDIAN 64) Type of 13 Centers 1 Center 1 Center Surgery Isoflurane Desflurane Sufentanil Desflurane Fentanyl Desflurane CABG 58 57 100 100 25 25 Abd Aorta 29 25 - - - - Periph Vasc 24 24 - - - - Carotid Art 45 46 - - - - Total 156 152 100 100 25 25 No differences were found in cardiovascular outcome (death, myocardial infarction, ventricular tachycardia or fibrillation, heart failure) among desflurane and the other anesthetics. Induction Desflurane should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or any patients where increases in heart rate or blood pressure are undesirable. In the desflurane vs sufentanil study, anesthetic induction with desflurane without opioids was associated with new transient ischemia in 14 patients vs 0 in the sufentanil group. In the desflurane group, mean heart rate, arterial pressure, and pulmonary blood pressure increased and stroke volume decreased in contrast to no change in the sufentanil group. Cardiovascular drugs were used frequently in both groups: especially esmolol in the desflurane group (56% vs 0%) and phenylephrine in the sufentanil group (43% vs 27%). When 10 µg/kg of fentanyl was used to supplement induction of anesthesia at one other center, continuous 2-lead ECG analysis showed a low incidence of myocardial ischemia and no difference between desflurane and isoflurane. If desflurane is to be used in patients with coronary artery disease, it should be used in combination with other medications for induction of anesthesia, preferably intravenous opioids and hypnotics. Maintenance & Recovery In studies where desflurane or isoflurane anesthesia was supplemented with fentanyl, there were no differences in hemodynamic variables or the incidence of myocardial 11 ischemia in the patients anesthetized with desflurane compared to those anesthetized with isoflurane. During the precardiopulmonary bypass period, in the desflurane vs sufentanil study where the desflurane patients received no intravenous opioid, more desflurane patients required cardiovascular adjuvants to control hemodynamics than the sufentanil patients. During this period, the incidence of ischemia detected by ECG or echocardiography was not statistically different between desflurane (18 of 99) and sufentanil (9 of 98) groups. However, the duration and severity of ECG-detected myocardial ischemia was significantly less in the desflurane group. The incidence of myocardial ischemia after cardiopulmonary bypass and in the ICU did not differ between groups. Geriatric Surgery SUPRANE (desflurane, USP) plus N2O was compared to isoflurane plus N2O in a multicenter study (6 sites) of 203 ASA physical status II or III elderly patients, aged 57 91 years (median 71). Induction Most patients were premedicated with fentanyl (mean 2 µg/kg), preoxygenated, and received thiopental (mean 4.3 mg/kg IV) or thiamylal (mean 4 mg/kg IV) followed by succinylcholine (mean 1.4 mg/kg IV) for intubation. Maintenance & Recovery Heart rate and arterial blood pressure remained within 20% of preinduction baseline values during administration of SUPRANE (desflurane, USP) 0.5-7.7% (average 3.6%) with 50-60% N2O. Induction, maintenance, and recovery cardiovascular measurements did not differ from those during isoflurane/N2O administration nor did the postoperative incidence of nausea and vomiting differ. The most common cardiovascular adverse event was hypotension occurring in 8% of the SUPRANE patients and 6% of the isoflurane patients. Neurosurgery SUPRANE (desflurane, USP) was studied in 38 patients aged 26-76 years (median 48 years), ASA physical status II or III undergoing neurosurgical procedures for intracranial lesions. Induction Induction consisted of standard neuroanesthetic techniques including hyperventilation and thiopental. 12 Maintenance No change in cerebrospinal fluid pressure (CSFP) was observed in 8 patients who had intracranial tumors when the dose of desflurane was 0.5 MAC in N2O 50%. In another study of 9 patients with intracranial tumors, 0.8 MAC desflurane/air/O2 did not increase CSFP above postinduction baseline values. In a different study of 10 patients receiving 1.1 MAC desflurane/air/O2, CSFP increased 7 mm Hg (range 3-13 mm Hg increase, with final values of 11-26 mm Hg) above the predrug values. All volatile anesthetics may increase intracranial pressure in patients with intracranial space occupying lesions. In such patients, desflurane should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) in the period before cranial decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure. The use of a lower dose of desflurane and the administration of a barbiturate and mannitol would be predicted to lessen the effect of desflurane on CSFP. Under hypocapnic conditions (PaCO2 27 mm Hg) desflurane 1 and 1.5 MAC did not increase cerebral blood flow (CBF) in 9 patients undergoing craniotomies. CBF reactivity to increasing PaCO2 from 27 to 35 mm Hg was also maintained at 1.25 MAC desflurane/air/O2. Pediatric Surgery SUPRANE (desflurane, USP) is not recommended for induction of anesthesia in pediatric patients because of the high incidence of moderate to severe upper airway adverse reactions, including laryngospasm, coughing, breathholding, and secretions, seen in studies of induction of anesthesia in pediatric patients. (see WARNINGS and PRECAUTIONS – Pediatric Use). SUPRANE is not approved for maintenance of anesthesia in non-intubated pediatric patients due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions, seen in one study of maintenance of anesthesia in non-intubated pediatric patients. (see WARNINGS and PRECAUTIONS – Pediatric Use). Maintenance & Recovery in Intubated Pediatric Patients SUPRANE (desflurane, USP) is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. 13 SUPRANE, with or without N2O, and halothane, with or without N2O were studied in three clinical trials of pediatric patients aged 2 weeks to 12 years (median 2 years) and ASA physical status I or II. The concentration of SUPRANE (desflurane, USP) required for maintenance of general anesthesia is age-dependent (see INDIVIDUALIZATION OF DOSE). Changes in blood pressure during maintenance of and recovery from anesthesia with desflurane/N2O/O2 are similar to those observed with halothane/N2O/O2. Heart rate during maintenance of anesthesia is approximately 10 beats per minute faster with desflurane than with halothane. Patients were judged fit for discharge from post- anesthesia care units within one hour with both desflurane and halothane. There were no differences in the incidence of nausea and vomiting between patients receiving desflurane or halothane. INDIVIDUALIZATION OF DOSE (Also see DOSAGE AND ADMINISTRATION) Preanesthetic Medication Issues such as whether or not to premedicate and the choice of premedicant(s) must be individualized. In clinical studies, patients scheduled to be anesthetized with desflurane frequently received IV preanesthetic medication, such as opioid and/or benzodiazepine. Induction In adults, some premedicated with opioid, a frequent starting concentration was 3% desflurane, increased in 0.5-1.0% increments every 2 to 3 breaths. End-tidal concentrations of 4-11% SUPRANE (desflurane, USP) with and without N2O, produced anesthesia within 2 to 4 minutes. When desflurane was tested as the primary anesthetic induction agent, the incidence of upper airway irritation (apnea, breathholding, laryngospasm, coughing and secretions) was high (see ADVERSE REACTIONS). During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO2 < 90%) was 6%. After induction in adults with an intravenous drug such as thiopental or propofol, desflurane can be started at approximately 0.5-1 MAC, whether the carrier gas is O2 or N2O/O2. Maintenance Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5-8.5% SUPRANE (desflurane, USP) with or without the concomitant use of nitrous oxide. In 14 children, surgical levels of anesthesia may be maintained with concentrations of 5.2-10% SUPRANE with or without the concomitant use of nitrous oxide. During the maintenance of anesthesia, increasing concentrations of SUPRANE (desflurane, USP) produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be due to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of desflurane exceeding 1 MAC may increase heart rate. Thus with this drug, an increased heart rate may not serve reliably as a sign of inadequate anesthesia. SUPRANE (desflurane, USP) decreases the doses of neuromuscular blocking agents required (see PRECAUTIONS, Drug Interactions). INDICATIONS AND USAGE SUPRANE (desflurane, USP) is indicated as an inhalation agent for induction and/or maintenance of anesthesia for inpatient and outpatient surgery in adults (see PRECAUTIONS). SUPRANE (desflurane, USP) is not recommended for induction of anesthesia in pediatric patients because of a high incidence of moderate to severe upper airway adverse events (see WARNINGS). After induction of anesthesia with agents other than SUPRANE, and tracheal intubation, SUPRANE is indicated for maintenance of anesthesia in infants and children. CONTRAINDICATIONS SUPRANE (desflurane, USP) should not be used in patients with a known or suspected genetic susceptibility to malignant hyperthermia. Known sensitivity to SUPRANE (desflurane, USP) or to other halogenated agents. WARNINGS Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these 15 cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. Malignant Hyperthermia In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, desflurane induced malignant hyperthermia. The clinical syndrome is signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia. Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible. Respiratory Adverse Reactions in Pediatric Patients SUPRANE (desflurane, USP) is not recommended for induction of general anesthesia via mask in children due to a high incidence of moderate to severe respiratory adverse reactions seen in clinical studies (see PRECAUTIONS – Pediatric Use). SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions (see PRECAUTIONS – Pediatric Use). Administration of Suprane SUPRANE (desflurane, USP) should be administered only by persons trained in the administration of general anesthesia, using a vaporizer specifically designed and designated for use with desflurane. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Hypotension and respiratory depression increase as anesthesia is deepened. 16 PRECAUTIONS During the maintenance of anesthesia, increasing concentrations of SUPRANE (desflurane, USP) produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be related to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of desflurane exceeding 1 MAC may increase heart rate. Thus an increased heart rate may not be a sign of inadequate anesthesia. In patients with intracranial space occupying lesions, SUPRANE (desflurane, USP) should be administered at 0.8 MAC or less, in conjunction with a barbiturate induction and hyperventilation (hypocapnia). Appropriate measures should be taken to maintain cerebral perfusion pressure (see CLINICAL TRIALS, Neurosurgery). In patients with coronary artery disease, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia. Desflurane should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or patients where increases in heart rate or blood pressure are undesirable. It should be used with other medications, preferably intravenous opioids and hypnotics (see CLINICAL TRIALS, Cardiovascular Surgery). Inspired concentrations of SUPRANE (desflurane, USP) greater than 12% have been safely administered to patients, particularly during induction of anesthesia. Such concentrations will proportionately dilute the concentration of oxygen; therefore, maintenance of an adequate concentration of oxygen may require a reduction of nitrous oxide or air if these gases are used concurrently. The recovery from general anesthesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU). SUPRANE (desflurane, USP), like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber cannister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of SUPRANE (desflurane, USP). 17 As with other halogenated anesthetic agents, SUPRANE (desflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see CONTRAINDICATIONS). Drug Interactions No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of desflurane on the disposition of other drugs has not been determined. Like isoflurane, desflurane does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine. Benzodiazepines and Opioids (MAC Reduction) Benzodiazepines (midazolam 25-50 µg/kg) decrease the MAC of desflurane by 16% as do the opioids (fentanyl 3-6 µg/kg) by 50% (see DOSAGE AND ADMINISTRATION). Neuromuscular Blocking Agents Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O/opioid anesthesia. The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied. DOSAGE OF MUSCLE RELAXANT CAUSING 95% DEPRESSION IN NEUROMUSCULAR BLOCKADE Mean ED95 (µg/kg) Desflurane Concentration Pancuronium Atracurium Succinylcholine 0.65 MAC 60% N2O/O2 26 123 - 1.25 MAC 60% N2O/O2 18 91 - 1.25 MAC O2 22 120 362 Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of desflurane. 18 Among nondepolarizing drugs, only pancuronium and atracurium interactions have been studied. In the absence of specific guidelines: 1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine. 2. During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N2O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation. Renal or Hepatic Insufficiency Nine patients receiving SUPRANE (desflurane, USP) (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either SUPRANE (desflurane, USP) (N=28) or isoflurane (N=30) undergoing renal transplant. Eight patients receiving SUPRANE (desflurane, USP) were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal carcinogenicity studies have not been performed with SUPRANE (desflurane, USP). In vitro and in vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by SUPRANE. Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay. Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility. 19 Pregnancy Teratogenic Effects No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery. Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. SUPRANE (desflurane, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rats exposed to desflurane at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. Body weight of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation. Labor and Delivery The safety of desflurane during labor or delivery has not been demonstrated. Nursing Mothers The concentrations of desflurane in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, desflurane concentrations in milk are predicted to be below those found with other volatile potent anesthetics. Pediatric Use SUPRANE (desflurane, USP) is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. SUPRANE is not recommended for induction of general anesthesia via mask in children because of the high incidence of moderate to severe respiratory adverse reactions, including laryngospasm (50%), coughing (72%), breathholding (68%), increase in secretions (21%) and oxyhemoglobin desaturation (SpO2 <90%) (26%) seen in clinical studies. 20 SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions (see below). In a clinical safety trial conducted in children aged 2 to 16 years (mean 7.4 years), following induction with another agent, SUPRANE and isoflurane (in N2O/O2) were compared when delivered via face mask or laryngeal mask airway (LMA) for maintenance of anesthesia, after induction with intravenous propofol or inhaled sevoflurane, in order to assess the relative incidence of respiratory adverse events. MAINTENANCE IN NONINTUBATED PEDIATRIC PATIENTS (FACE MASK OR LMA USED; N=300) All Respiratory Events (>1% of All Pediatric Patients) All Ages 2-6 yr 7-11 yr 12-16 yr (N=300) (N=150) (N=81) (N=69) Any respiratory 39% 42% 33% 39% events Airway obstruction 4% 5% 4% 3% Breath-holding 3% 2% 3% 4% Coughing 26% 33% 19% 22% Laryngospasm 13% 16% 7% 13% Secretion 12% 13% 10% 12% Non-specific 2% 2% 1% 1% desaturation Minor, moderate and severe respiratory events SUPRANE was associated with higher rates (compared with isoflurane) of coughing, laryngospasm and secretions with an overall rate of respiratory events of 39%. Of the pediatric patients exposed to desflurane, 5% experienced severe laryngospasm (associated with significant desaturation; i.e. SpO2 of <90% for >15 seconds, or requiring succinylcholine), across all ages, 2-16 years old. Individual age group incidences of severe laryngospasm were 9% for 2-6 years old, 1% for 7-11 years old, and 1% for 12-16 years old. Removal of LMA under deep anesthesia (MAC range 0.6 – 2.3 with a mean of 1.12 MAC) was associated with a further increase in frequency of respiratory adverse events as compared to awake LMA removal or LMA removal under deep anesthesia with the comparator. The frequency and severity of non-respiratory adverse events were comparable between the two groups. 21 The incidence of respiratory events under these conditions was highest in children aged 2-6 years. Therefore, similar studies in children under the age of 2 years were not initiated. Geriatric Use The average MAC for SUPRANE (desflurane, USP) in a 70 year old patient is two-thirds the MAC for a 20 year old patient (see DOSAGE AND ADMINISTRATION). Neurosurgical Use SUPRANE (desflurane, USP) may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. Desflurane should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in CSFP. Appropriate attention must be paid to maintain cerebral perfusion pressure (see CLINICAL STUDIES, Neurosurgery). ADVERSE REACTIONS Adverse event information is derived from controlled clinical trials, the majority of which were conducted in the United States. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered. Of the 2,143 patients exposed to SUPRANE (desflurane, USP) in clinical trials, 370 adults and 152 children were induced with desflurane alone and 987 patients were maintained principally with desflurane. The frequencies given reflect the percent of patients with the event. Each patient was counted once for each type of adverse event. They are presented in alphabetical order according to body system. Frequency of Events Occurring in Greater Than 1% of Clinical Trial Patients (in Reports Deemed “Probably Causally Related”) Induction (use as a mask inhalation agent) ADULT PATIENTS Coughing 34%, breathholding 30%, apnea 15%, increased (N=370): secretions, laryngospasm, oxyhemoglobin desaturation (SpO2 < 90%), pharyngitis. 22 Maintenance or Recovery ADULT AND INTUBATED PEDIATRIC PATIENTS (N=687): Body as a Whole Headache Cardiovascular Bradycardia, hypertension, nodal arrhythmia, tachycardia Digestive Nausea 27%, vomiting 16% Nervous system Increased salivation Respiratory Apnea, breathholding, cough increased, laryngospasm, pharyngitis Special Senses Conjunctivitis (conjunctival hyperemia) * Incidence of events: 3% - 10% Frequency of Events Occurring in Less Than 1% of Patient(in Reports Deemed “Probably Causally Related”) Reported in 3 or more patients, regardless of severity Adverse reactions reported only from postmarketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized. Cardiovascular Arrhythmia, bigeminy, abnormal electrocardiogram, myocardial ischemia, vasodilation Digestive Hepatitis Nervous System Agitation, dizziness Respiratory Asthma, dyspnea, hypoxia Frequency of Events Occurring in Less Than 1% of Clinical Trial Patients (in Reports Deemed “Causal Relationship Unknown”) Reported in 3 or more patients, regardless of severity Body as a Whole Fever Cardiovascular Hemorrhage, myocardial infarct Metabolic and Nutrition Increased creatinine phosphokinase Musculoskeletal System Myalgia Skin and Appendages Pruritus See WARNINGS for information regarding pediatric use and malignant hyperthermia. 23 Post Marketing Reports The following adverse reactions have been identified during post-approval use of SUPRANE (desflurane, USP). Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. BLOOD AND LYMPHATIC SYSTEM DISORDERS: Coagulopathy METABOLISM AND NUTRITION DISORDERS: Hyperkalemia, Hypokalemia, Metabolic acidosis NERVOUS SYSTEM DISORDERS: Convulsion EYE DISORDERS: Ocular icterus CARDIAC DISORDERS: Cardiac arrest, Torsade de pointes, Ventricular failure, Ventricular hypokinesia VASCULAR DISORDERS: Malignant hypertension, Hemorrhage, Hypotension, Shock RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Respiratory arrest, Respiratory failure, Respiratory distress, Bronchospasm, Hemoptysis GASTROINTESTINAL DISORDERS: Pancreatitis acute, Abdominal pain HEPATOBILIARY DISORDERS: Hepatic failure, Hepatic necrosis, Cytolytic hepatitis, Cholestasis, Jaundice, Hepatic function abnormal, Liver disorder SKIN AND SUBCUTANEOUS TISSUE DISORDER: Urticaria, Erythema, MUSCULOSKELETAL, CONNECTIVE TISSUE, AND BONE DISORDERS: Rhabdomyolysis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Hyperthermia malignant, Asthenia, Malaise INVESTIGATIONS: Tranaminases increased, Alanine aminotransferase increased, Aspartate aminotransferase increased, Coagulation test abnormal, Ammonia increased 24 INJURY, POISONING, AND PROCEDURAL COMPLICATIONS: Tachyarrhythmia, Palpitations, Eye burns, Blindness transient, Encephalopathy, Ulcerative keratitis, Ocular hyperemia, Visual acuity reduced, Eye irritation, Eye pain, Dizziness, Migraine, Fatigue, Accidental exposure, Skin burning sensation, Drug administration error All of reactions categorized within this SOC were accidental exposures to non-patients. Laboratory Findings Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents. DRUG ABUSE AND DEPENDENCE The potential drug abuse liability, and dependence associated with SUPRANE (desflurane, USP) have not been studied. OVERDOSAGE In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of SUPRANE (desflurane, USP), maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. DOSAGE AND ADMINISTRATION Deliver SUPRANE (desflurane, USP) from a vaporizer specifically designed and designated for use with desflurane. The administration of general anesthesia must be individualized based on the patient’s response (see INDIVIDUALIZATION OF DOSE). The following two tables provide mean relative potency based upon age and drug interaction studies in predominately ASA physical status I or II patients. 25 EFFECT OF AGE ON MAC OF DESFLURANE MEAN ± SD (percent atmospheres) Age N O2 100% N N2O 60% 2 weeks 6 9.2 ± 0.0 - - 10 weeks 5 9.4 ± 0.4 - - 9 months 4 10.0 ± 0.7 5 7.5 ± 0.8 2 years 3 9.1 ± 0.6 - - 3 years - - 5 6.4 ± 0.4 4 years 4 8.6 ± 0.6 - - 7 years 5 8.1 ± 0.6 - - 25 years 4 7.3 ± 0.0 4 4.0 ± 0.3 45 years 4 6.0 ± 0.3 6 2.8 ± 0.6 70 years 6 5.2 ± 0.6 6 1.7 ± 0.4 N = number of crossover pairs (using up-and-down method of quantal response) Opioids or benzodiazepines decrease the amounts of SUPRANE (desflurane, USP) required to produce anesthesia. The following table is based on studies of drug interaction (MAC reduction). SUPRANE (desflurane, USP) MAC WITH FENTANYL OR MIDAZOLAM MEAN ± SD (percent reduction) Dose 18-30 years 31-65 years No fentanyl 6.4 ± 0.0 6.3 ± 0.4 3 µg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%) 6 µg/kg fentanyl 3.0 ± 1.2 (53%) 2.3 ± 1.0 (64%) No midazolam 6.9 ± 0.1 5.9 ± 0.6 25 µg/kg midazolam - 4.9 ± 0.9 (16%) 50 µg/kg midazolam - 4.9 ± 0.5 (17%) SUPRANE (desflurane, USP) decreases the doses of neuromuscular blocking agents required (see PRECAUTIONS, Drug Interactions). During the maintenance of anesthesia with inflow rates of 2 L/min or more, the alveolar concentration of desflurane will usually be within 10% of the inspired concentration. (FA/FI, see Figure 1 in Pharmacokinetics section). 26 HOW SUPPLIED SUPRANE (desflurane, USP), NDC 10019-641-24, is packaged in amber-colored bottles containing 240 mL desflurane. Safety and Handling Occupational Caution There is no specific work exposure limit established for SUPRANE (desflurane, USP). However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour. The predicted effects of acute overexposure by inhalation of SUPRANE (desflurane, USP) include headache, dizziness or (in extreme cases) unconsciousness. There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. Storage Store at room temperature, 15°-30°C (59°-86°F). SUPRANE (desflurane, USP) has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle cap should be replaced after each use of SUPRANE. Baxter and SUPRANE are trademarks of Baxter International Inc. logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA 27 For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-00070/10.0 28	custom-source	2025-02-12T13:46:45.896006	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020118s016lbl.pdf', 'application_number': 20118, 'submission_type': 'SUPPL ', 'submission_number': 16}
12,224	_______________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Suprane safely and effectively. See full prescribing information for Suprane. Suprane (desflurane, USP) Volatile Liquid for Inhalation Initial U.S. Approval: 1992 ----------------------------INDICATIONS AND USAGE--------------------------- Suprane is an inhalation agent indicated: • for induction and/or maintenance of anesthesia in adults (1.1) • for maintenance of anesthesia in pediatric patients following induction with agents other than Suprane and intubation. Suprane is not recommended for induction of anesthesia in pediatric patients. (1.2) ----------------------DOSAGE AND ADMINISTRATION----------------------- • Suprane should be administered only by persons trained in the administration of general anesthesia. It should only be administered using a vaporizer specifically designed and designated for use with Suprane. (2) • The administration of general anesthesia must be individualized based on the patient’s response, including cardiovascular and pulmonary changes. (2) • Suprane should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or where increases in heart rate or blood pressure are undesirable. (2.6) • Patients with intracranial space occupying lesions (2.7) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- • Volatile liquid for inhalation, 100% Suprane (3) -------------------------------CONTRAINDICATIONS----------------------------- • Patients with known or suspected genetic susceptibility to malignant hyperthermia (4) • Patients in whom general anesthesia is contraindicated (4) • Patients with known sensitivity to halogenated agents (4, 5.3) -----------------------WARNINGS AND PRECAUTIONS----------------------- • Malignant hyperthermia may occur. (5.1) • Perioperative hyperkalemia may occur. Patients with latent or overt neuromuscular disease, particularly with Duchenne muscular dystrophy, appear to be most vulnerable. (5.2) • Suprane may cause sensitivity hepatitis in patients sensitized by previous exposure to halogenated anesthetics. (4, 5.3) • Suprane is not recommended as an induction agent in children or for maintenance of anesthesia in non-intubated children due to a high incidence of moderate to severe respiratory adverse reactions, including coughing, laryngospasm and secretions. (5.4, 8.4) • Suprane can react with desiccated CO2 absorbents to produce carbon monoxide. (5.5) • There are no adequate or well-controlled studies in pregnant or lactating women or during labor and delivery. Suprane is a uterine relaxant. (8.1, 8.2, 8.3) ------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (incidence> 10%) are coughing, breath holding, apnea, nausea, vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-800-262-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- • Concomitant use of N2O, benzodiazepines and/or opioids reduces the MAC of Suprane. Adjust dose accordingly. (7.1, 7.3) • Suprane decreases the doses of neuromuscular blocking agents required. Adjust dose accordingly. (7.2) -----------------------USE IN SPECIFIC POPULATIONS------------------------ • Pediatric: Suprane is not recommended as an induction agent in children or for maintenance of anesthesia in non-intubated children due to an increased incidence of moderate to severe respiratory adverse reactions, including coughing, laryngospasm and secretions. (5.4, 8.4) • Geriatric: The minimum alveolar concentration (MAC) of Suprane decreases with increasing patient age. (8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: [2/2010] FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Induction of Anesthesia in Adults 1.2 Maintenance of Anesthesia 2 DOSAGE AND ADMINISTRATION 2.1 Preanesthetic Medication 2.2 Induction 2.3 Maintenance 2.4 Maintenance of Anesthesia in Intubated Pediatric Patients 2.5 Recovery 2.6 Use in Patients with Coronary Artery Disease 2.7 Neurosurgical Use 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Malignant Hyperthermia 5.2 Perioperative Hyperkalemia 5.3 Respiratory Adverse Reactions in Pediatric Patients 5.4 Interactions with Desiccated Carbon Dioxide Absorbents 5.5 Hepatobiliary Disorders 5.6 Laboratory Findings 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Benzodiazepines and Opioids (MAC Reduction) 7.2 Neuromuscular Blocking Agents 7.3 Concomitant use with N20 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Pharmacodynamics 12.2 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Ambulatory Surgery 14.2 Cardiovascular Surgery 14.3 Geriatric Surgery 14.4 Neurosurgery 14.5 Pediatric Surgery 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safety and Handling 16.2 Storage 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 2 of 31 Full Prescribing Information (FPI) FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE 1.1 Induction of Anesthesia in Adults SUPRANE is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults. SUPRANE is not recommended for induction of anesthesia in pediatric patients because of a high incidence of moderate to severe upper airway adverse events [see Warnings and Precautions (5.4)]. 1.2 Maintenance of Anesthesia SUPRANE is indicated as an inhalation agent for maintenance of anesthesia for inpatient and outpatient surgery in adults and in pediatric patients. After induction of anesthesia with agents other than SUPRANE, and tracheal intubation, SUPRANE is indicated for maintenance of anesthesia in infants and children. SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm, and secretions [see Warnings and Precautions (5.4) and Clinical Studies (14.5)]. 2. DOSAGE AND ADMINISTRATION Only persons trained in the administration of general anesthesia should administer SUPRANE. Only a vaporizer specifically designed and designated for use with SUPRANE, should be utilized for its administration. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. SUPRANE is administered by inhalation. The administration of general anesthesia must be individualized based on the patient’s response. Hypotension and respiratory depression increase as anesthesia with Suprane is deepened. The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. The MAC for SUPRANE is also reduced by concomitant N2O administration (see Table 1). The dose should be adjusted accordingly. The following table provides mean relative potency based upon age and effect of N2O in predominately ASA physical status I or II patients. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 3 of 31 Full Prescribing Information (FPI) Benzodiazepines and opioids decrease the MAC of SUPRANE. [see Drug Interactions (7.1, Table 3)]. SUPRANE also decreases the doses of neuromuscular blocking agents required [see Drug Interactions (7.2, Table 4)]. The dose should be adjusted accordingly. Table 1 Effect of Age on Minimum Alveolar Concentration of SUPRANE Mean ± SD (percent atmospheres) Age N O2 100% N N2O 60%/40% O2 2 weeks 6 9.2 ± 0.0 - - 10 weeks 5 9.4 ± 0.4 - - 9 months 4 10.0 ± 0.7 5 7.5 ± 0.8 2 years 3 9.1 ± 0.6 - - 3 years - - 5 6.4 ± 0.4 4 years 4 8.6 ± 0.6 - - 7 years 5 8.1 ± 0.6 - - 25 years 4 7.3 ± 0.0 4 4.0 ± 0.3 45 years 4 6.0 ± 0.3 6 2.8 ± 0.6 70 years 6 5.2 ± 0.6 6 1.7 ± 0.4 N = number of crossover pairs (using up-and-down method of quantal response) 2.1 Preanesthetic Medication Issues such as whether or not to premedicate and the choice of premedication(s) must be individualized. In clinical studies, patients scheduled to be anesthetized with SUPRANE frequently received IV preanesthetic medication, such as opioid and/or benzodiazepine. 2.2 Induction In adults, some premedicated with opioid, a frequent starting concentration was 3% SUPRANE, increased in 0.5-1.0% increments every 2 to 3 breaths. End-tidal concentrations of 4-11%, SUPRANE with and without N2O, produced anesthesia within 2 to 4 minutes. When SUPRANE was tested as the primary anesthetic induction agent, the incidence of upper airway irritation (apnea, breathholding, laryngospasm, coughing and secretions) was high. During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO2 < 90%) was 6% [see Adverse Reactions (6.1)]. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 4 of 31 Full Prescribing Information (FPI) After induction in adults with an intravenous drug such as thiopental or propofol, SUPRANE can be started at approximately 0.5-1 MAC, whether the carrier gas is O2 or N2O/O2. Inspired concentrations of SUPRANE greater than 12% have been safely administered to patients, particularly during induction of anesthesia. Such concentrations will proportionately dilute the concentration of oxygen; therefore, maintenance of an adequate concentration of oxygen may require a reduction of nitrous oxide or air if these gases are used concurrently. 2.3 Maintenance Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5-8.5% SUPRANE with or without the concomitant use of nitrous oxide. In children, surgical levels of anesthesia may be maintained with concentrations of 5.2-10% SUPRANE with or without the concomitant use of nitrous oxide. During the maintenance of anesthesia with inflow rates of 2 L/min or more, the alveolar concentration of SUPRANE will usually be within 10% of the inspired concentration. [FA/FI, see Figure 2 in Clinical Pharmacology (12.3)] During the maintenance of anesthesia, increasing concentrations of SUPRANE produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be due to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE. Concentrations of SUPRANE exceeding 1 MAC may increase heart rate. Thus with this drug, an increased heart rate may not serve reliably as a sign of inadequate anesthesia. 2.4 Maintenance of Anesthesia in Intubated Pediatric Patients SUPRANE is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. SUPRANE, with or without N2O, and halothane, with or without N2O were studied in three clinical trials of pediatric patients aged 2 weeks to 12 years (median 2 years) and ASA physical status I or II. The concentration of SUPRANE required for maintenance of general anesthesia is age-dependent. [see Clinical Studies (14.5)] Changes in blood pressure during maintenance of and recovery from anesthesia with SUPRANE /N2O/O2 are similar to those observed with halothane/N2O/O2. Heart rate during maintenance of anesthesia is approximately 10 beats per minute faster with Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 5 of 31 Full Prescribing Information (FPI) SUPRANE than with halothane. Patients were judged fit for discharge from post- anesthesia care units within one hour with both SUPRANE and halothane. There were no differences in the incidence of nausea and vomiting between patients receiving SUPRANE or halothane. 2.5 Recovery The recovery from general anesthesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU). 2.6 Use in Patients with Coronary Artery Disease In patients with coronary artery disease, maintenance of normal hemodynamics is important to prevent myocardial ischemia. SUPRANE should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or patients where increases in heart rate or blood pressure are undesirable. It should be used with other medications, preferably intravenous opioids and hypnotics [see Clinical Studies (14.2)]. 2.7 Neurosurgical Use SUPRANE may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. SUPRANE should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in CSFP. Appropriate attention must be paid to maintain cerebral perfusion pressure [see Clinical Studies (14.4)]. 3. DOSAGE FORMS AND STRENGTHS Colorless, non-flammable, volatile liquid (below 22.8°C) for inhalation, 100% SUPRANE 4. CONTRAINDICATIONS The use of SUPRANE is contraindicated in the following conditions: • Known or suspected genetic susceptibility to malignant hyperthermia. • Patients in whom general anesthesia is contraindicated. • Patients with known sensitivity to SUPRANE or to other halogenated agents [see Warnings and Precautions (5.3)]. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 6 of 31 Full Prescribing Information (FPI) 5. WARNINGS AND PRECAUTIONS 5.1 Malignant Hyperthermia In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, SUPRANE induced malignant hyperthermia. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia. Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible. 5.2 Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. 5.3 Respiratory Adverse Reactions in Pediatric Patients SUPRANE is not recommended for induction of general anesthesia via mask in children due to a high incidence of moderate to severe respiratory adverse reactions, including laryngospasm, coughing, breathholding, and secretion seen in clinical studies [see Clinical Studies (14.5)]. SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions [see Clinical Studies (14.5)]. Caution should be exercised Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 7 of 31 Full Prescribing Information (FPI) when SUPRANE is used for maintenance anesthesia with laryngeal mask airway (LMA) in children 6 years old or younger because of the increased potential for adverse respiratory events, e.g. coughing and laryngospasm, especially with removal of the LMA under deep anesthesia [see Pediatric Use (8.4)]. 5.4 Interactions with Desiccated Carbon Dioxide Absorbents Desflurane, like some other inhalation anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide that may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 canister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of SUPRANE. 5.5 Hepatobiliary Disorders With the use of halogenated anesthetics, disruption of hepatic function, icterus and fatal liver necrosis have been reported; such reactions appear to indicate hypersensitivity. As with other halogenated anesthetic agents, SUPRANE may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics [see Contraindications (4)]. Cirrhosis, viral hepatitis or other pre-existing hepatic disease may be a reason to select an anesthetic other than a halogenated anesthetic. As with all halogenated anesthetics, repeated anesthesia within a short period of time should be approached with caution. 5.6 Laboratory Findings Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents. 1. ADVERSE REACTIONS 6.1 Clinical Trials Experience Adverse event information is derived from controlled clinical trials, the majority of which were conducted in the United States. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered. Of the 2,143 patients exposed to SUPRANE in clinical trials, 370 adults and 152 children were induced with SUPRANE alone and 987 patients were maintained principally with SUPRANE. The frequencies given reflect the percent of patients with the event. Each Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 8 of 31 Full Prescribing Information (FPI) patient was counted once for each type of adverse event. They are presented in alphabetical order according to body system. Table 2. Frequency of Events Occurring in Greater Than 1% of Clinical Trial Patients (in Reports Deemed “Probably Causally Related”) Induction (use as a mask inhalation agent) Adult Patients (N=370) : Coughing 34%, breathholding 30%, apnea 15%, increased secretions, laryngospasm, oxyhemoglobin desaturation (SpO2 < 90%), pharyngitis. Maintenance or Recovery Adult and Intubated Pediatric Patients (N=687): Body as a Whole Headache Cardiovascular Bradycardia, hypertension, nodal arrhythmia, tachycardia Digestive Nausea 27%, vomiting 16% Nervous system Increased salivation Respiratory Apnea, breathholding, cough increased, laryngospasm, pharyngitis Special Senses Conjunctivitis (conjunctival hyperemia) Incidence of events 3% - 10% Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 9 of 31 Full Prescribing Information (FPI) Frequency of Events Occurring in Less Than 1% of Patient (in Reports Deemed “Probably Causally Related”) Reported in 3 or more patients, regardless of severity Adverse reactions reported only from postmarketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized. Cardiovascular Arrhythmia, bigeminy, abnormal electrocardiogram, myocardial ischemia, vasodilation Digestive Hepatitis Nervous System Agitation, dizziness Respiratory Asthma, dyspnea, hypoxia Frequency of Events Occurring in Less Than 1% of Clinical Trial Patients (in Reports Deemed “Causal Relationship Unknown”) Reported in 3 or more patients, regardless of severity Body as a Whole Fever Cardiovascular Hemorrhage, myocardial infarct Metabolic and Nutrition Increased creatinine phosphokinase Musculoskeletal System Myalgia Skin and Appendages Pruritus 6.2 Post Marketing Experience The following adverse reactions have been identified during post-approval use of SUPRANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Coagulopathy Metabolism and Nutrition Disorders: Hyperkalemia, Hypokalemia, metabolic acidosis Nervous System Disorders: Convulsion Eye Disorders: Ocular icterus Cardiac Disorders: Cardiac arrest, Torsade de pointes, ventricular failure, ventricular hypokinesia Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 10 of 31 Full Prescribing Information (FPI) Vascular Disorders: Malignant hypertension, hemorrhage, hypotension, shock Respiratory, Thoracic and Mediastinal Disorders: Respiratory arrest, respiratory failure, respiratory distress, bronchospasm, hemoptysis Gastrointestinal Disorders: Pancreatitis acute, abdominal pain Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, cytolytic hepatitis, cholestasis, jaundice, hepatic function abnormal, liver disorder Skin and Subcutaneous Tissue Disorder: Urticaria, erythema, Musculoskeletal, Connective Tissue and Bone Disorders: Rhabdomyolysis General Disorders and Administration Site Conditions: Hyperthermia malignant, asthenia, malaise Investigations: Electrocardiogram ST-T change, electrocardiogram T-wave inversion, tranaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, coagulation test abnormal, ammonia increased Injury, Poisoning, and Procedural Complications: Tachyarrhythmia, palpitations, eye burns, blindness transient, encephalopathy, ulcerative keratitis, ocular hyperemia, visual acuity reduced, eye irritation, eye pain, dizziness, migraine, fatigue, accidental exposure, skin burning sensation, drug administration error All of reactions categorized within this SOC were accidental exposures to non-patients. 7. DRUG INTERACTIONS No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of SUPRANE on the disposition of other drugs has not been determined. Similar to isoflurane, SUPRANE does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 11 of 31 Full Prescribing Information (FPI) 7.1 Benzodiazepines and Opioids (MAC Reduction) Benzodiazepines and opioids decrease the amount of desflurane (MAC) needed to produce anesthesia. This effect is shown in Table 3 for intravenous midazolam (25-50 µg/kg) and intravenous fentanyl (3-6 µg/kg) in patients of two different age groups. Table 3 SUPRANE MAC with Fentanyl or Midazolam Mean ± SD (percent reduction) Dose 18-30 years 31-65 years No fentanyl 6.4 ± 0.0 6.3 ± 0.4 3 µg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%) 6 µg/kg fentanyl 3.0 ± 1.2 (53%) 2.3 ± 1.0 (64%) No midazolam 6.9 ± 0.1 5.9 ± 0.6 25 µg/kg midazolam - 4.9 ± 0.9 (16%) 50 µg/kg midazolam - 4.9 ± 0.5 (17%) 7.2 Neuromuscular Blocking Agents Anesthetic concentrations of SUPRANE at equilibrium (administered for 15 or more minutes before testing) reduced the ED95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O/opioid anesthesia (see Table 4). The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied. Table 4 DOSAGE OF MUSCLE RELAXANT CAUSING 95% DEPRESSION IN NEUROMUSCULAR BLOCKADE Mean ED95 (µg/kg) SUPRANE Concentration Pancuronium Atracurium Succinylcholine Vecuronium 0.65 MAC 60% N2O/O2 26 123 - - 1.25 MAC 60% N2O/O2 18 91 - - 1.25 MAC O2 22 120 362 19 Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 12 of 31 Full Prescribing Information (FPI) Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of SUPRANE. Among nondepolarizing drugs, pancuronium, atracurium, and vecuronium interactions have been studied. In the absence of specific guidelines: 1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine. 2. During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N2O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation. 7.3 Concomitant Use with N2O Concomitant administration of N2O reduces the MAC of SUPRANE [see Dosage and Administration (2), Table 1]. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B.There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats at doses up to at 1 MAC hour for a minimum of 21 days and have revealed no evidence of impaired fertility or harm to the fetus due to SUPRANE. No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery. Rats exposed to SUPRANE at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. Body weights of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 13 of 31 Full Prescribing Information (FPI) 8.2 Labor and Delivery The safety of SUPRANE during labor or delivery has not been demonstrated. SUPRANE is a uterine-relaxant. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SUPRANE is administered to a nursing woman. 8.4 Pediatric Use Respiratory Adverse Reactions in Pediatric Patients SUPRANE is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation. SUPRANE is not recommended for induction of general anesthesia via mask in children because of the high incidence of moderate to severe respiratory adverse reactions, including laryngospasm (50%), coughing (72%), breathholding (68%), increase in secretions (21%) and oxyhemoglobin desaturation (SpO2 <90%) (26%) seen in clinical studies [see Clinical Studies (14.5)]. SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions [see Clinical Studies (14.5)]. Caution should be exercised when SUPRANE is used for maintenance anesthesia with laryngeal mask airway (LMA) in children 6 years old or younger because of the increased potential for adverse respiratory events, e.g. coughing and laryngospasm, especially with removal of the LMA under deep anesthesia [see Warnings and Precautions (5.4)]. 8.5 Geriatric Use The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. The dose should be adjusted accordingly. The average MAC for SUPRANE in a 70 year old patient is two-thirds the MAC for a 20 year old patient [see Dosage and Administration (2) Table 1 and Clinical Studies (14.3)]. 8.6 Renal Impairment Concentrations of 1-4% SUPRANE in nitrous oxide/oxygen have been used in patients with chronic renal or hepatic impairment and during renal transplantation surgery. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 14 of 31 Full Prescribing Information (FPI) Because of minimal metabolism, a need for dose adjustment in patients with renal and hepatic impairment is not to be expected. Nine patients receiving SUPRANE (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either SUPRANE (N=28) or isoflurane (N=30) undergoing renal transplant. 8.7 Hepatic Impairment Eight patients receiving SUPRANE were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen. 10. OVERDOSAGE The symptoms of overdosage of SUPRANE can present as a deepening of anesthesia, cardiac and/or respiratory depression in spontaneously breathing patients, and cardiac depression in ventilated patients in whom hypercapnia and hypoxia may occur only at a late stage. In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of SUPRANE, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. 11. DESCRIPTION SUPRANE, a nonflammable liquid administered via vaporizer, is a general inhalation anesthetic. It is (±)1,2,2,2-tetrafluoroethyl difluoromethyl ether: Molecular Structure Some physical constants are: Molecular weight 168.04 Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 15 of 31 Full Prescribing Information (FPI) Specific gravity (at 20°C/4°C) 1.465 Vapor pressure in mm Hg 669 mm Hg @ 20°C 731 mm Hg @ 22°C 757 mm Hg @ 22.8°C (boiling point;1atm) 764 mm Hg @ 23°C 798 mm Hg @ 24°C 869 mm Hg @ 26°C Partition coefficients at 37°C: Blood/Gas 0.424 Olive Oil/Gas 18.7 Brain/Gas 0.54 Mean Component/Gas Partition Coefficients: Polypropylene (Y piece) 6.7 Polyethylene (circuit tube) 16.2 Latex rubber (bag) 19.3 Latex rubber (bellows) 10.4 Polyvinylchloride (endotracheal tube) 34.7 SUPRANE is nonflammable as defined by the requirements of International Electrotechnical Commission 601-2-13. SUPRANE is a colorless, volatile liquid below 22.8°C. Data indicate that SUPRANE is stable when stored under normal room lighting conditions according to instructions. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 16 of 31 Full Prescribing Information (FPI) SUPRANE is chemically stable. The only known degradation reaction is through prolonged direct contact with soda lime producing low levels of fluoroform (CHF3). The amount of CHF3 obtained is similar to that produced with MAC-equivalent doses of isoflurane. No discernible degradation occurs in the presence of strong acids. SUPRANE does not corrode stainless steel, brass, aluminum, anodized aluminum, nickel plated brass, copper, or beryllium. 12. CLINICAL PHARMACOLOGY 12.1 Pharmacodynamics Changes in the clinical effects of SUPRANE rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for SUPRANE are given in the following tables: In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5 2.0 µg/kg), anesthesia was initiated with propofol 2.5 mg/kg, SUPRANE /N2O 60% in O2 or SUPRANE /O2 alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, SUPRANE 2.6-8.4% in N2O 60% in O2, or SUPRANE 3.1-8.9% in O2. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 17 of 31 Full Prescribing Information (FPI) EMERGENCE AND RECOVERY AFTER OUTPATIENT LAPAROSCOPY 178 FEMALES, AGES 20-47 TIMES IN MINUTES: MEAN ± SD (RANGE) Induction: Propofol Propofol SUPRANE /N2O SUPRANE /O2 Maintenance: Propofol/N2O SUPRANE /N2O SUPRANE /N2O SUPRANE /O2 Number of Pts: N = 48 N = 44 N = 43 N = 43 —–––– ——— ——— ——— Median age 30 26 29 30 (20 - 43) (21 - 47) (21 - 42) (20 - 40) Anesthetic 49 ± 53 45 ± 35 44 ± 29 41 ± 26 Time (8 - 336) (11 - 178) (14 - 149) (19 - 126) Time to open 7 ± 3 5 ± 2 5 ± 2* 4 ± 2* eyes (2 - 19) (2 - 10) (2 - 12) (1 - 11) Time to state 9 ± 4 8 ± 3 7 ± 3* 7 ± 3* name (4 - 22) (3 - 18) (3 - 16) (2 - 15) Time to stand 80 ± 34 86 ± 55 81 ± 38 77 ± 38 (40 - 200) (30 - 320) (35 - 190) (35 - 200) Time to walk 110 ± 6 122 ± 85 108 ± 59 108 ± 66 (47 - 285) (37 – 375) (48 - 220) (49 - 250) Time to fit for 152 ± 75 157 ± 80 150 ± 66 155 ± 73 discharge (66 - 375) (73 - 385) (68 - 310) (69 - 325) ———————————————————————————————————— Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the propofol-propofol/N2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 18 of 31 Full Prescribing Information (FPI) In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or SUPRANE in O2. Anesthesia was maintained with isoflurane 0.7-1.4% in N2O 60%, SUPRANE 1.8-7.7% in N2O 60%, or SUPRANE 4.4-11.9% in O2. EMERGENCE AND RECOVERY TIMES IN OUTPATIENT SURGERY 46 MALES, 42 FEMALES, AGES 19-70 TIMES IN MINUTES: MEAN ± SD (RANGE) Induction: Thiopental Thiopental Thiopental SUPRANE /O2 Maintenance: Isoflurane/N2O SUPRANE /N2O SUPRANE /O2 SUPRANE /O2 Number of Pts: N = 23 N = 21 N = 23 N = 21 ——– ——– —––– ——– Median age 43 40 43 41 (20 - 70) (22 - 67) (19 - 70) (21-64) Anesthetic 49 ± 23 50 ± 19 50 ± 27 51 ± 23 Time (11 - 94) (16 - 80) (16 - 113) (19 - 117) Time to open 13 ± 7 9 ± 3 12 ± 8 8 ± 2* eyes (5 - 33) (4 - 16) (4 - 39) (4 - 13) Time to state 17 ± 10 11 ± 4* 15 ± 10 9 ± 3* name (6 - 44) (6 - 19) (6 - 46) (5 - 14) Time to walk 195 ± 67 176 ± 60 168 ± 34 181 ± 42 (124 - 365) (101 - 315) (119 - 258) (92 - 252) Time to fit for 205 ± 53 202 ± 41 197 ± 35 194 ± 37 discharge (153 - 365) (144 - 315) (155 - 280) (134 - 288) ———————————————————————————————————— Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the thiopental-isoflurane/N2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 19 of 31 Full Prescribing Information (FPI) Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC SUPRANE (3%) or isoflurane (0.6%) in N2O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of the isoflurane group were able to perform the psychometric tests compared to 76% in the SUPRANE group (p < 0.05). RECOVERY TESTS: PERCENT OF PREOPERATIVE BASELINE VALUES 16 MALES, 22 FEMALES, AGES 20-65 PERCENT: MEAN ± SD 60 minutes After Anesthesia 90 minutes After Anesthesia Maintenance: SUPRANE/N2O Isoflurane/N2O SUPRANE/N2O Isoflurane/N2O Confusion Δ 66 ± 6 47 ± 8 75 ± 7 56 ± 8 Fatigue Δ 70 ± 9* 33 ± 6 89 ± 12* 47 ± 8 Drowsiness Δ 66 ± 5* 36 ± 8 76 ± 7* 49 ± 9 Clumsiness Δ 65 ± 5 49 ± 8 80 ± 7* 57 ± 9 Comfort Δ 59 ± 7* 30 ± 6 60 ± 8* 31 ± 7 DSST+ score 74 ± 4* 50 ± 9 75 ± 4* 55 ± 7 Trieger Tests++ 67 ± 5 74 ± 6 90 ± 6 83 ± 7 Δ Visual analog scale (values from 0-100; 100 = baseline) + DSST = Digit Symbol Substitution Test ++ Trieger Test = Dot Connecting Test * Differences were statistically significant (p < 0.05) using a two-sample t-test Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 20 of 31 Full Prescribing Information (FPI) SUPRANE was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO2 38 mm Hg) were: HEMODYNAMIC EFFECTS OF SUPRANE DURING CONTROLLED VENTILATION 12 MALE VOLUNTEERS, AGES 16-26 MEAN ± SD (RANGE) Mean Arterial Heart Rate Cardiac Index Pressure (beats/min) (L/min/m2) (mm Hg) End- End- Total MAC Tidal % Tidal % Equivalent Des/O2 Des/N2O O2 N2O O2 N2O O2 N2O ———— ———— ———— — ––– — ––– — — 0 0% / 21% 0% / 0% 69 ± 4 70 ± 6 85 ± 9 85 ± 9 3.7 ± 0.4 3.7 ± 0.4 (63 - 76) (62 - 85) (74 - 102) (74 - 102) (3.0 - 4.2) (3.0 - 4.2) 0.8 6% / 94% 3% / 60% 73 ± 5 77 ± 8 61 ± 5* 69 ± 5* 3.2 ± 0.5 3.3 ± 0.5 (67 - 80) (67 - 97) (55 - 70) (62 - 80) (2.6 - 4.0) (2.6 - 4.1) 1.2 9% / 91% 6% / 60% 80 ± 5* 77 ± 7 59 ± 8* 63 ± 8* 3.4 ± 0.5 3.1 ± 0.4* (72 - 84) (67 - 90) (44 - 71) (47 - 74) (2.6 - 4.1) (2.6 - 3.8) 1.7 12% / 88% 9% / 60% 94 ± 14* 79 ± 9 51 ± 12* 59 ± 6* 3.5 ± 0.9 3.0 ± 0.4* (78 - 109) (61 - 91) (31 - 66) (46 - 68) (1.7 - 4.7) (2.4 - 3.6) Differences were statistically significant (p < 0.05) compared to awake values, Newman-Keul’s method of multiple comparison. When the same volunteers breathed spontaneously during SUPRANE anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation. During spontaneous ventilation in the same volunteers, increasing the concentration of SUPRANE from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N2O 60% with a given concentration of SUPRANE gave results similar to those with SUPRANE alone. Respiratory depression produced by SUPRANE is similar to that produced by other potent inhalation agents. The use of SUPRANE concentrations higher than 1.5 MAC may produce apnea. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 21 of 31 Full Prescribing Information (FPI) Figure 1. PaCO2 During Spontaneous Ventilation in Unstimulated Volunteers Graph Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 22 of 31 Full Prescribing Information (FPI) 12.2 Pharmacokinetics Due to the volatile nature of SUPRANE in plasma samples, the washin-washout profile of SUPRANE was used as a surrogate of plasma pharmacokinetics. SUPRANE is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the SUPRANE absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of SUPRANE 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were measured. The FA/FI (washin) value at 30 minutes for SUPRANE was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane (see Figure 2). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for SUPRANE than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for SUPRANE, 0.22 for isoflurane, and 0.25 for halothane (see Figure 3). The washout for SUPRANE was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for SUPRANE is 1/20th of that for halothane or isoflurane. Graph Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 23 of 31 Full Prescribing Information (FPI) Graph 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal carcinogenicity studies have not been performed with SUPRANE. In vitro and in vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by SUPRANE. Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay. Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility. 14. CLINICAL STUDIES The efficacy of SUPRANE was evaluated in 1,843 patients including ambulatory (N=1,061), cardiovascular (N=277), geriatric (N=103), neurosurgical (N=40), and pediatric (N=235) patients. Clinical experience with these patients and with 1,087 control patients in these studies not receiving SUPRANE is described below. Although SUPRANE can be used in adults for the inhalation induction of anesthesia via mask, it produces a high incidence of respiratory irritation (coughing, breathholding, apnea, Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 24 of 31 Full Prescribing Information (FPI) increased secretions, laryngospasm). Oxyhemoglobin saturation below 90% occurred in 6% of patients (from pooled data, N = 370 adults). 14.1 Ambulatory Surgery SUPRANE plus N2O was compared to isoflurane plus N2O in multicenter studies (21 sites) of 792 ASA physical status I, II, or III patients aged 18-76 years (median 32). Induction Anesthetic induction begun with thiopental and continued with SUPRANE was associated with a 7% incidence of oxyhemoglobin saturation of 90% or less (from pooled data, N = 307) compared with 5% in patients in whom anesthesia was induced with thiopental and isoflurane (from pooled data, N = 152). Maintenance & Recovery SUPRANE with or without N2O or other anesthetics was generally well tolerated. There were no differences between SUPRANE and the other anesthetics studied in the times that patients were judged fit for discharge. In one outpatient study, patients received a standardized anesthetic consisting of thiopental 4.2-4.4 mg/kg, fentanyl 3.5-4.0 µg/kg, vecuronium 0.05-0.07 mg/kg, and N2O 60% in oxygen with either SUPRANE 3% or isoflurane 0.6%. Emergence times were significantly different; but times to sit up and discharge were not different (see Table 5). TABLE 5 RECOVERY PROFILES AFTER SUPRANE 3% IN N2O 60% vs ISOFLURANE 0.6% IN N2O 60% IN OUTPATIENTS 16 MALES, 22 FEMALES, AGES 20-65 MEAN ± SD Isoflurane SUPRANE Number 21 17 Anesthetic time (min) 127 ± 80 98 ± 55 Recovery time to: Follow commands 11.1 ± 7.9 6.5 ± 2.3 (min) Sit up (min) 113 ± 27 95 ± 56 Fit for discharge (min) 231 ± 40 207 ± 54 ———————————————————————————————————— Difference was statistically significant from the isoflurane group (p < 0.05), unadjusted for multiple comparisons. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ____ ____ ____ _____ ____ ____ Suprane Page 25 of 31 Full Prescribing Information (FPI) 14.2 Cardiovascular Surgery SUPRANE was compared to isoflurane, sufentanil or fentanyl for the anesthetic management of coronary artery bypass graft (CABG), abdominal aortic aneurysm, peripheral vascular and carotid endarterectomy surgery in 7 studies at 15 centers involving a total of 558 patients. In all patients except the SUPRANE vs. sufentanil study, the volatile anesthetics were supplemented with intravenous opioids, usually fentanyl. Blood pressure and heart rate were controlled by changes in concentration of the volatile anesthetics or opioids and cardiovascular drugs if necessary. Oxygen (100%) was the carrier gas in 253 of 277 SUPRANE cases (24 of 277 received N2O/O2). CARDIOVASCULAR PATIENTS BY AGENT AND TYPE OF SURGERY 418 MALES, 140 FEMALES, AGES 27-87 (MEDIAN 64) Type of 13 Centers 1 Center 1 Center Surgery Isoflurane SUPRANE Sufentanil SUPRANE Fentanyl SUPRANE CABG 58 57 100 100 25 25 Abd Aorta 29 25 - - - - Periph Vasc 24 24 - - - - Carotid Art 45 46 - - - - Total 156 152 100 100 25 25 No differences were found in cardiovascular outcome (death, myocardial infarction, ventricular tachycardia or fibrillation, heart failure) among SUPRANE and the other anesthetics. Induction SUPRANE should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or any patients where increases in heart rate or blood pressure are undesirable. In the SUPRANE vs. sufentanil study, anesthetic induction with SUPRANE without opioids was associated with new transient ischemia in 14 patients vs. 0 in the sufentanil group. In the SUPRANE group, mean heart rate, arterial pressure, and pulmonary blood pressure increased and stroke volume decreased in contrast to no change in the sufentanil group. Cardiovascular drugs were used frequently in both groups: especially esmolol in the SUPRANE group (56% vs. 0%) and phenylephrine in the sufentanil group (43% vs. 27%). When 10 µg/kg of fentanyl was used to supplement induction of anesthesia at one other center, continuous 2-lead ECG analysis showed a low Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 26 of 31 Full Prescribing Information (FPI) incidence of myocardial ischemia and no difference between SUPRANE and isoflurane. If SUPRANE is to be used in patients with coronary artery disease, it should be used in combination with other medications for induction of anesthesia, preferably intravenous opioids and hypnotics. Maintenance & Recovery In studies where SUPRANE or isoflurane anesthesia was supplemented with fentanyl, there were no differences in hemodynamic variables or the incidence of myocardial ischemia in the patients anesthetized with SUPRANE compared to those anesthetized with isoflurane. During the precardiopulmonary bypass period, in the SUPRANE vs. sufentanil study where the SUPRANE patients received no intravenous opioid, more SUPRANE patients required cardiovascular adjuvants to control hemodynamics than the sufentanil patients. During this period, the incidence of ischemia detected by ECG or echocardiography was not statistically different between SUPRANE (18 of 99) and sufentanil (9 of 98) groups. However, the duration and severity of ECG-detected myocardial ischemia was significantly less in the SUPRANE group. The incidence of myocardial ischemia after cardiopulmonary bypass and in the ICU did not differ between groups. 14.3 Geriatric Surgery SUPRANE plus N2O was compared to isoflurane plus N2O in a multicenter study (6 sites) of 203 ASA physical status II or III elderly patients, aged 57-91 years (median 71). Induction Most patients were premedicated with fentanyl (mean 2 µg/kg), preoxygenated, and received thiopental (mean 4.3 mg/kg IV) or thiamylal (mean 4 mg/kg IV) followed by succinylcholine (mean 1.4 mg/kg IV) for intubation. Maintenance & Recovery Heart rate and arterial blood pressure remained within 20% of preinduction baseline values during administration of SUPRANE 0.5-7.7% (average 3.6%) with 50-60% N2O. Induction, maintenance, and recovery cardiovascular measurements did not differ from those during isoflurane/N2O administration nor did the postoperative incidence of nausea and vomiting differ. The most common cardiovascular adverse event was hypotension occurring in 8% of the SUPRANE patients and 6% of the isoflurane patients. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 27 of 31 Full Prescribing Information (FPI) 14.4 Neurosurgery SUPRANE was studied in 38 patients aged 26-76 years (median 48 years), ASA physical status II or III undergoing neurosurgical procedures for intracranial lesions. Induction Induction consisted of standard neuroanesthetic techniques including hyperventilation and thiopental. Maintenance No change in cerebrospinal fluid pressure (CSFP) was observed in 8 patients who had intracranial tumors when the dose of SUPRANE was 0.5 MAC in N2O 50%. In another study of 9 patients with intracranial tumors, 0.8 MAC SUPRANE /air/O2 did not increase CSFP above post induction baseline values. In a different study of 10 patients receiving 1.1 MAC SUPRANE /air/O2, CSFP increased 7 mm Hg (range 3-13 mm Hg increase, with final values of 11-26 mm Hg) above the pre-drug values. All volatile anesthetics may increase intracranial pressure in patients with intracranial space occupying lesions. In such patients, SUPRANE should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) in the period before cranial decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure. The use of a lower dose of SUPRANE and the administration of a barbiturate and mannitol would be predicted to lessen the effect of SUPRANE on CSFP. Under hypocapnic conditions (PaCO2 27 mm Hg) SUPRANE 1 and 1.5 MAC did not increase cerebral blood flow (CBF) in 9 patients undergoing craniotomies. CBF reactivity to increasing PaCO2 from 27 to 35 mm Hg was also maintained at 1.25 MAC SUPRANE /air/O2. 14.5 Pediatric Surgery In a clinical safety trial conducted in children aged 2 to 16 years (mean 7.4 years), following induction with another agent, SUPRANE and isoflurane (in N2O/O2) were compared when delivered via face mask or laryngeal mask airway (LMA) for maintenance of anesthesia, after induction with intravenous propofol or inhaled sevoflurane, in order to assess the relative incidence of respiratory adverse events. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 28 of 31 Full Prescribing Information (FPI) MAINTENANCE IN NONINTUBATED PEDIATRIC PATIENTS (FACE MASK OR LMA USED; N=300) All Respiratory Events (>1% of All Pediatric Patients) All Ages 2-6 yr 7-11 yr 12-16 yr (N=300) (N=150) (N=81) (N=69) Any respiratory 39% 42% 33% 39% events Airway obstruction 4% 5% 4% 3% Breath-holding 3% 2% 3% 4% Coughing 26% 33% 19% 22% Laryngospasm 13% 16% 7% 13% Secretion 12% 13% 10% 12% Non-specific 2% 2% 1% 1% desaturation Minor, moderate and severe respiratory events SUPRANE was associated with higher rates (compared with isoflurane) of coughing, laryngospasm and secretions with an overall rate of respiratory events of 39%. Of the pediatric patients exposed to SUPRANE, 5% experienced severe laryngospasm (associated with significant desaturation; i.e. SpO2 of <90% for >15 seconds, or requiring succinylcholine), across all ages, 2-16 years old. Individual age group incidences of severe laryngospasm were 9% for 2-6 years old, 1% for 7-11 years old, and 1% for 12-16 years old. Removal of LMA under deep anesthesia (MAC range 0.6 – 2.3 with a mean of 1.12 MAC) was associated with a further increase in frequency of respiratory adverse events as compared to awake LMA removal or LMA removal under deep anesthesia with the comparator. The frequency and severity of non-respiratory adverse events were comparable between the two groups. The incidence of respiratory events under these conditions was highest in children aged 2-6 years. Therefore, similar studies in children under the age of 2 years were not initiated. 16. HOW SUPPLIED/STORAGE AND HANDLING SUPRANE, NDC 10019-641-24, is packaged in amber-colored bottles containing 240 mL SUPRANE. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 29 of 31 Full Prescribing Information (FPI) 16.1 Safety and Handling Occupational Caution There is no specific work exposure limit established for SUPRANE. However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour. Principle routes of exposure include: Skin contact – May cause skin irritation. In case of contact, immediately flush skin with plenty of water. Remove contaminated clothing and shoes. Seek medical attention if irritation develops. Eye contact – May cause eye irritation. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Seek medical attention if irritation develops. Ingestion – No specific hazards other than therapeutic effects. Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. If large quantities of this material are swallowed, seek medical attention immediately. Inhalation – If individuals smell vapors, or experience dizziness or headaches, they should be moved to an area with fresh air. Individuals could also experience the following: Cardiovascular effects: may include fluctuations in heart rate, changes in blood pressure, chest pain. Respiratory effects: may include shortness of breath, bronchospasms, laryngospasms, respiratory depression. Gastrointestinal effects: may include nausea, upset stomach, loss of appetite. Nervous System effects: may include ataxia, tremor, disturbance of speech, lethargy, headache, dizziness, blurred vision. The predicted effects of acute overexposure by inhalation of SUPRANE include headache, dizziness or (in extreme cases) unconsciousness. [see Overdosage (10)] There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 30 of 31 Full Prescribing Information (FPI) studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system; work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. Consistent with clinical data, concentrations would need to reach 2-3% in inspired air before individuals would likely experience dizziness or other physiologic effects. 16.2 Storage Store at room temperature, 15°-30°C (59°-86°F). SUPRANE has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle should be recapped after each use of SUPRANE. 17. PATIENT COUNSELING INFORMATION Anesthesia providers need to obtain the following information from patients prior to administration of anesthesia: • Medications they are taking, including herbal supplements • Drug allergies, including allergic reactions to anesthetic agents (including hepatic sensitivity) • Any history of severe reactions to prior administration of anesthetic • If the patient or a member of the patient’s family has a history of malignant hyperthermia or if the patient has a history of Duchenne muscular dystrophy or other latent neuromuscular disease Anesthesia providers should inform patients of the risks associated with SUPRANE: • Post-operative nausea and vomiting and respiratory adverse effects including coughing. • There is no information of the effects of SUPRANE following anesthesia on the ability to operate an automobile or other heavy machinery. However, patients should be advised that the ability to perform such tasks may be impaired after receiving anesthetic agents. Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Suprane Page 31 of 31 Full Prescribing Information (FPI) ********************************************************************* Baxter and SUPRANE are trademarks of Baxter International Inc. Company logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA ********************************************************************** Revised 02/2010 MLT-00070/11.0 Baxter Confidential This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:46.085429	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020118s017lbl.pdf', 'application_number': 20118, 'submission_type': 'SUPPL ', 'submission_number': 17}
12,226	Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 1 ))))))))))))))))))))))))))))))))))))))))))) D R A F T TRI-NASAL SPRAY (triamcinolone ® acetonide nasal spray, 50 mcg) For Intranasal Use Only DESCRIPTION: Triamcinolone acetonide, the active ingredient of Tri-Nasal Spray, is a corticosteroid ® with the chemical name, 9"-Fluoro- $,16", 17, 21-tetrahydroxypregna- 1,4-diene-3, 20-dione cyclic 16, 17- acetal with acetone (C H FO ). Its 24 31 6 structural formula is: Triamcinolone acetonide, USP, is a white crystalline powder, with a molecular weight of 434.51. It is practically insoluble in water, and sparingly soluble in dehydrated alcohol, in chloroform and in methanol. It has a melting point temperature range between 292o and 294 C. o Tri-Nasal Spray is a metered-dose ® manual spray pump in an amber polyethylene terephthalate (PET) bottle with 0.05% w/v triamcinolone acetonide in a solution This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 2 ))))))))))))))))))))))))))))))))))))))))))) containing citric acid, edetate available topical corticosteroids are disodium, polyethylene glycol 3350, not as effective as treatment with propylene glycol, purified water, sodium citrate, and 0.01% benzalkonium chloride as a preservative. Tri-Nasal Spray pH is ® 5.3. After initial priming (three sprays) of the Tri-Nasal Spray metered pump ® delivery system, each spray will deliver 50 mcg of triamcinolone acetonide. If the pump was not used for more than 14 days, reprime with 3 sprays or until a fine mist is observed. The majority of the droplets produced by the pump are 8 microns or greater. Each 15 mL bottle contains 7.5 mg of triamcinolone acetonide to deliver 120 metered sprays. After 120 sprays, the amount of triamcinolone acetonide delivered per spray may not be consistent and the bottle should be discarded. CLINICAL PHARMACOLOGY: Triamcinolone acetonide is a more potent derivative of triamcinolone. Triamcinolone acetonide is approximately eight times more potent than prednisone in animal models of inflammation. Although the precise mechanism of corticosteroid antiallergic action is unknown, corticosteroids are very effective. When allergic symptoms are very severe, local treatment with recommended doses (microgram) of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 3 ))))))))))))))))))))))))))))))))))))))))))) larger doses (milligram) of oral or All three metabolites are expected parenteral formulations. to be Pharmacokinetics: Absorption: The pharmacokinetics of Tri-Nasal Spray was evaluated in ® a single- dose study conducted in 24 patients with perennial allergic rhinitis. Following a single intranasal dose of 400 mcg of triamcinolone acetonide (twice the recommended starting dose of Tri- Nasal Spray), the mean C of the ® max drug was 1.12 ng/mL (SD = 0.38) with a median T of 0.5 hours max (range: 0.08 - 1.0). A pharmacokinetic study to demonstrate dose proportionality was conducted in patients with perennial allergic rhinitis. The Cmax and AUC of the 200 and 400 mcg doses increased less than proportionally when compared to the 100 mcg dose. Following multiple dosing (100 or 200 or 400 mcg QD for 7 days), there was no evidence of drug accumulation. Distribution: The volume of distribution (Vd) reported was 99.5 L (SD = 27.5). Metabolism: In animal studies using rats and dogs, three metabolites of triamcinolone acetonide have been identified. They are 6$- hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6$- hydroxytriamcinolone acetonide. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 4 ))))))))))))))))))))))))))))))))))))))))))) substantially less active than the pharmacokinetics of Tri-Nasal parent compound due to (a) the Spray dependence of anti-inflammatory activity on the presence of a 21- hydroxyl group, (b) the decreased activity observed upon 6- hydroxylation, and (c) the markedly increased water solubility favoring rapid elimination. There appeared to be some quantitative differences in the metabolites among species. No differences were detected in metabolic pattern as a function of route of administration. Elimination: After a single intranasal dose of 400 mcg of triamcinolone acetonide (twice the recommended starting dose of Tri-Nasal Spray), ® the mean observed elimination half- life was 2.26 hours (SD=0.77). Based upon intravenous dosing of triamcinolone acetonide phosphate ester, the half-life of triamcinolone acetonide was reported to be 88 minutes. The reported clearance was 45.2 L/hour (SD=9.1) for triamcinolone acetonide. Special populations Age: The effect of age, specifically in geriatric and pediatric patients, on the pharmacokinetics of triamcinolone acetonide has not been studied. Gender: Gender did not significantly influence the pharmacokinetics of Tri-Nasal Spray. ® Race: The effect of race on the ® This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 5 ))))))))))))))))))))))))))))))))))))))))))) has not been studied. completed 8 controlled clinical Renal/Hepatic Insufficiency: No specific pharmacokinetic studies have been conducted in renally or hepatically impaired subjects. Drug-Drug Interactions: No specific drug-drug interactions have been investigated. Pharmacodynamics: A small (approximately 5 to 7 patients per treatment group), parallel trial was conducted to assess the effect of Tri-Nasal Spray ® on the Hypothalamic-Pituitary- Adrenal (HPA) axis. Patients with allergic rhinitis were treated for six weeks with 400 mcg, 800 mcg, or 1600 mcg total daily doses of Tri-Nasal Spray, 10 mg oral ® prednisone once daily, or placebo. Adrenal response to a six-hour cosyntropin stimulation test suggests that intranasal Tri-Nasal® Spray 400 mcg/day for six weeks did not measurably affect adrenal activity. Tri-Nasal treatment arms ® using doses of 800 and 1600 mcg/day demonstrated a trend toward dose-related suppression of HPA response. However, this decrease did not reach statistical significance, whereas 10 mg daily oral prednisone did. CLINICAL TRIALS: The efficacy of Tri-Nasal Spray has been evaluated ® in 746 patients with seasonal or perennial allergic rhinitis who trials. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 6 ))))))))))))))))))))))))))))))))))))))))))) In total, 1187 patients have been topical corticosteroid can be treated with Tri-Nasal Spray in the ® clinical development program. Three adequate and well controlled multi-center trials involving 541 patients with seasonal allergic rhinitis who received doses of Tri- Nasal Spray ranging from 50 mcg ® to 400 mcg once daily were conducted. The results showed that patients who received $ 200 mcg daily of the active drug had statistically significant relief in the severity of nasal symptoms of seasonal allergic rhinitis including sneezing, stuffiness, discharge, and itching, compared to those receiving placebo. In one clinical trial that examined efficacy after 2 days of 200 or 400 mcg Tri-Nasal Spray treatment, ® only the 400 mcg dose showed statistically significant improvement over placebo in the nasal symptoms of seasonal allergic rhinitis. INDICATIONS AND USAGE: Tri- Nasal Spray is indicated for the ® treatment of the nasal symptoms of seasonal and perennial allergic rhinitis in adults and children 12 years of age or older. CONTRAINDICATIONS: Hypersensitivity to any of the ingredients of this preparation contraindicates its use. WARNINGS: The replacement of a systemic corticosteroid with a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 7 ))))))))))))))))))))))))))))))))))))))))))) accompanied by signs of adrenal General: Intranasal corticosteroids insufficiency and, in addition, some may cause a reduction in growth patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to Tri-Nasal Spray ® should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions which require long-term corticosteroid treatment, too rapid a decrease in systemic corticosteroid may cause a severe exacerbation of their symptoms. Persons who are on immuno- suppressant drugs are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in children or adults on immunosuppressant doses of corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. PRECAUTIONS: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 8 ))))))))))))))))))))))))))))))))))))))))))) velocity when administered to consistent with accepted pediatric patients ( see procedures PRECAUTIONS, Pediatric Use section). In clinical studies with triamcinolone acetonide nasal spray, the development of localized infections of the nose and pharynx with Candida albicans has rarely occurred. When such an infection develops it may require treatment with appropriate local therapy and discontinuance of treatment with Tri-Nasal Spray. ® Tri-Nasal Spray should be used with ® caution, if at all, in patients with active or quiescent tuberculous infection of the respiratory tract or in patients with untreated fungal, bacterial, or systemic viral infections or ocular herpes simplex. Because of the inhibitory effect of corticosteroids on wound healing, in patients who have experienced recent nasal septal ulcers, nasal surgery or trauma, a corticosteroid should be used with caution until healing has occurred. As with other nasally inhaled corticosteroids, nasal septal perforations have been reported in rare instances. When used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, Tri-Nasal Spray ® should be discontinued slowly, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 9 ))))))))))))))))))))))))))))))))))))))))))) for discontinuing oral corticosteroid corticosteroids should be warned to therapy. avoid exposure Systemic Availability and HPA Axis Suppression: Triamcinolone acetonide administered intranasally as Tri-Nasal Spray has been shown ® to be absorbed into the systemic circulation in humans. The bioavailability of triamcinolone acetonide when administered as a solution in Tri-Nasal Spray is ® approximately 5-fold greater than when administered as a CFC aerosol suspension formulation. While Tri- Nasal Spray administered to 5 ® patients with allergic rhinitis at 400 mcg/day for 42 days did not measurably affect adrenal response to a six-hour cosyntropin stimulation test, the 6-hour cosyntropin test is an insensitive assessment for subtle HPA effects of corticosteroids. Doses of 800 and 1600 mcg/day of Tri-Nasal Spray did demonstrate a ® trend toward dose-related suppression of the HPA response. However, this decrease did not reach statistical significance, whereas 10 mg daily oral prednisone did. (see Clinical Pharmacology, Pharmacodynamics) Information for Patients: Patients being treated with Tri- Nasal Spray should receive the ® following information and instructions. •Patients who are on immuno- suppressant doses of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 10 ))))))))))))))))))))))))))))))))))))))))))) to chickenpox or measles and, if exposed, to obtain medical advice. •The bottle should be discarded •Patients should use Tri-Nasal® Spray at regular intervals since its effectiveness depends on its regular use. (See DOSAGE AND ADMINISTRATION) •An improvement in some patient symptoms may be seen within the first two days of treatment, and generally, it takes one week of treatment to reach maximum benefit. •The patient should take the medication as directed and should not exceed the prescribed dosage. The patient should contact the physician if symptoms do not improve after three weeks, or if the condition worsens. •Patients who experience recurrent episodes of epistaxis (nose bleeds) or nasal septum discomfort while taking this medication should contact their physician. Transient nasal irritation and/or burning or stinging may occur upon instillation with this product. Spraying triamcinolone acetonide directly onto the nasal septum should be avoided. •For the proper use of this unit and to attain maximum improvement, the patient should read and follow the accompanying patient instructions carefully. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 11 ))))))))))))))))))))))))))))))))))))))))))) after 120 sprays since the amount Zealand White rabbits treated of triamcinolone acetonide delivered thereafter per spray may not be consistent. Carcinogenesis, Mutagenesis and Impairment of Fertility: In two-year mouse and Sprague-Dawley rat studies, triamcinolone acetonide did not increase the incidence of tumors at oral doses up to 1 and 3 mcg/kg, respectively (less than the maximum recommended daily intranasal dose on a mcg/m basis). 2 The genotoxic potential of triamcinolone acetonide has not been studied. Triamcinolone acetonide did not impair fertility in Sprague-Dawley rats given oral doses up to 15 mcg/kg (less than the maximum recommended daily intranasal dose on a mcg/m basis). 2 However, triamcinolone acetonide caused increased fetal resorptions and stillbirths and decreased pup weight and survival at 5 mcg/kg (less than the maximum recommended daily intranasal dose on a mcg/m basis). These effects 2 were not produced at 1 mcg/kg (less than the maximum recommended daily intranasal dose on a mcg/m basis). 2 Pregnancy: Pregnancy Category C. Triamcinolone acetonide induced cleft palate, internal hydrocephaly and skeletal defects in fetuses of Sprague-Dawley rats and New This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 12 ))))))))))))))))))))))))))))))))))))))))))) throughout organogenesis with daily observed. inhalation doses of 20 mcg/kg (less than the maximum recommended daily intranasal dose on a mcg/m2 basis). Triamcinolone acetonide induced cranial malformations in fetuses of Rhesus monkeys treated throughout organogenesis with daily intramuscular doses of 500 mcg/kg and greater (approximately 20 times the maximum recommended daily intranasal dose on a mcg/m basis). 2 The 500 mcg/kg dose was the lowest dose used in this study. There are no adequate and well- controlled studies in pregnant women. Triamcinolone acetonide should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Since their introduction, experience with oral corticosteroids in pharmacologic as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. N o n t e r a t o g e n i c E f f e c t s : Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 13 ))))))))))))))))))))))))))))))))))))))))))) Nursing Mothers: It is not known treatment alternatives. To minimize whether triamcinolone acetonide is the systemic effects of intranasal excreted in human breast milk. Because other corticosteroids are excreted in human milk, caution should be exercised when Tri- Nasal Spray is administered to ® nursing women. Pediatric Use: Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including Tri-Nasal Spray should be ® monitored routinely (e.g. via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 14 ))))))))))))))))))))))))))))))))))))))))))) corticosteroids, including Tri-Nasal® Spray, each patient should be titrated to the lowest dose that effectively controls his/her systems. Adverse Reactions: In adequate, well-controlled and uncontrolled studies, 1187 patients have received Tri-Nasal Spray. The ® adverse reactions summarized below, are based upon seven placebo controlled clinical trials of 2-6 weeks duration in 847 patients with seasonal or perennial allergic rhinitis (504 patients received 200 mcg or 400 mcg per day of Tri- Nasal Spray and 343 patients ® received vehicle placebo). Adverse events reported by 2% or more of patients (regardless of relationship to treatment) who received Tri- Nasal Spray 200 or 400 mcg once ® daily and that were more common with Tri-Nasal Spray than with ® placebo are displayed in the table below. Overall, the incidence and nature of adverse events with Tri- Nasal 400 mcg was comparable to ® that seen with Tri-Nasal 200 mcg ® and with vehicle placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 15 ))))))))))))))))))))))))))))))))))))))))))) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 16 ))))))))))))))))))))))))))))))))))))))))))) ADVERSE EVENTS REPORTED AT A FREQUENCY OF 2% OR GREATER AND MORE COMMON AMONG PATIENTS TREATED WITH TRI-NASAL SPRAY THAN PLACEBO ® REGARDLESS OF RELATIONSHIP TO TREATMENT ADVERSE EVENTS 200 mcg of 400 mcg of (200 and 400 triamcinolone triamcinolone mcg) use of acetonide acetonide triamcinolone Vehicle once daily once daily acetonide Placebo n = 204 n = 300 n = 504 n = 343 Combined BODY AS A WHOLE HEADACHE 51.0% 44.3% 47.0% 41.1% BACK PAIN 7.8% 4.7% 6.0% 3.5% RESPIRATORY SYSTEM PHARYNGITIS 13.7% 10.3% 11.7% 7.9% ASTHMA 5.4% 4.3% 4.8% 2.9% COUGH INCREASED 2.0% 2.7% 2.4% 2.3% DIGESTIVE SYSTEM DYSPEPSIA 4.9% 2.7% 3.6% 2.0% NAUSEA 2.0% 3.0% 2.6% 0.6% VOMITING 1.5% 2.7% 2.2% 1.5% SPECIAL SENSES TASTE PERVERSION 7.8% 5.0% 6.2% 2.9% CONJUNCTIVITIS 4.4% 1.3% 2.6% 1.5% MUSCULOSKELETAL SYSTEM MYALGIA 2.5% 3.3% 3.0% 2.6% Adverse events reported by 2% or and uncontrolled studies, more of patients who received Tri- approximately 0.3% of patients Nasal Spray 200 or 400 mcg once ® daily and that were more common with placebo than with Tri-Nasal® Spray included: application site reaction (e.g. transient nasal burning and stinging), rhinitis, dysmenorrhea, pain (unspecified) and allergic reaction. The adverse effects related to the irritation of nasal mucous membranes (i.e. application site reaction) did not usually interfere with treatment. In the controlled This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 17 ))))))))))))))))))))))))))))))))))))))))))) discontinued because of irritation given either as a once a day of nasal mucous membranes. dosage (4 sprays in each nostril) or In the event of accidental divided overdose, an increased potential for these adverse experiences may be expected, but systemic adverse experiences are unlikely. (see OVERDOSE section) Cases of growth suppression have been reported for intranasal corticosteroids. (see PRECAUTIONS, Pediatric Use section). OVERDOSAGE: Like any other nasally administered corticosteroid, acute overdosage is unlikely. The acute topical application of the entire 15 mL of the bottle would most likely cause nasal irritation and headache. Significant acute systemic adverse effects are unlikely even if the entire 7.5 mg of triamcinolone acetonide is administered intranasally at one time. The intranasal median lethal dose has not been determined in animals. Dosage and Administration The usual recommended starting dose of Tri-Nasal Spray for most ® patients is 200 mcg per day given as 2 sprays (approximately 50 mcg/spray) in each nostril once a day. The maximum dose should not exceed 400 mcg per day. If the 400 mcg dose is used, it may be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 18 ))))))))))))))))))))))))))))))))))))))))))) into two daily doses of two symptoms sooner when started on sprays/nostril twice a day. The nasal spray pump must be primed before Tri-Nasal Spray is ® used for the first time. To prime the pump, press down on the shoulder of the white nasal applicator using your forefinger and middle finger while supporting the base of the bottle with your thumb. Press down and release the pump until it sprays 3 times or until a fine mist is observed (see DIRECTIONS FOR USE). INDIVIDUALIZATION OF DOSAGE: Dosing of Tri-Nasal Spray should ® be individualized since there are many variables that determine clinical response. These variables include the degree of patient allergy and degree of pollen exposure, both of which may influence the dose required. A starting dose of 200 mcg (2 sprays/nostril) once daily is recommended for most patients. If the patient does not receive a satisfactory response from the initial 200 mcg/day starting dose, the dose may be increased to a maximum of 400 mcg (4 sprays/nostril) once daily. An alternative 400 mcg per day dosing regimen may be given as 200 mcg twice daily (two 50 mcg sprays in each nostril twice daily). Some patients may obtain relief of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 19 ))))))))))))))))))))))))))))))))))))))))))) a 400 mcg per day dose of Tri- Directions for Use: Illustrated Nasal Spray than with 200 mcg patient instructions for use ® per day. Onset of significant relief accompany each package of of nasal symptoms was seen within two days after starting treatment at 400 mcg once daily. A starting dose of 400 mcg per day may be considered in patients when starting therapy with Tri-Nasal® Spray in cases where a faster onset of relief is desirable. Generally, maximum relief of symptoms may take several days or up to one week to occur. After symptoms have been brought under control, patients should be titrated to the minimum effective dose to reduce the possibility of adverse effects. If relief of symptoms is not achieved after 14-21 days of Tri- Nasal Spray therapy given in an ® adequate dose, Tri-Nasal Spray ® should be discontinued and alternative diagnosis and therapies considered. The maximum daily dose should not exceed 400 mcg. (see PRECAUTIONS, WARNINGS, INFORMATION FOR PATIENTS and ADVERSE REACTIONS sections). Tri-Nasal Spray is not ® recommended for use in persons under 12 years of age since its safety and effectiveness have not been established in this age group. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Muro Pharmaceutical, Inc. Tri-Nasal Spray ® NDA #20-120 Amendment Page 20 ))))))))))))))))))))))))))))))))))))))))))) Tri-Nasal Spray. ® HOW SUPPLIED: Each 15 mL bottle of Tri-Nasal Spray (NDC# ® 0451-5050-15) contains 7.5 mg (0.50 mg/mL) of triamcinolone acetonide, USP and is fitted with a meter pump with white nasal applicator, teal blue dust cover and teal blue locking clip sealed in a foil pouch. The unit delivers 120 metered sprays and comes with a patient’s instructions for use leaflet. Do not spray in eyes. Store at controlled room temperature: 20 -25 C (68 -77 F). Protect from o o o o freezing. Use Tri-Nasal spray within 3 ® months after opening of the protective foil pouch or before expiration date, whichever comes first. L only Muro Pharmaceutical, Inc. Tewksbury, MA 01876 I-5050 Revision 2/2000 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:46.093833	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20120lbl.pdf', 'application_number': 20120, 'submission_type': 'ORIG ', 'submission_number': 1}
12,225	VUMON® (teniposide injection) WARNING VUMON (teniposide injection) is a cytotoxic drug which should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available. Severe myelosuppression with resulting infection or bleeding may occur. Hypersensitivity reactions, including anaphylaxis-like symptoms, may occur with initial dosing or at repeated exposure to VUMON. Epinephrine, with or without corticosteroids and antihistamines, has been employed to alleviate hypersensitivity reaction symptoms. DESCRIPTION VUMON® (teniposide injection) (also commonly known as VM-26), is supplied as a sterile nonpyrogenic solution in a nonaqueous medium intended for dilution with a suitable parenteral vehicle prior to intravenous infusion. VUMON is available in 50 mg (5 mL) ampules. Each mL contains 10 mg teniposide, 30 mg benzyl alcohol, 60 mg N,N-dimethylacetamide, 500 mg purified Cremophor® EL (polyoxyethylated castor oil), and 42.7% (v/v) dehydrated alcohol. The pH of the clear solution is adjusted to approximately 5 with maleic acid. Cremophor® EL is the registered trademark of BASF Aktiengesellschaft. Cremophor® EL is further purified by a Bristol-Myers Squibb Company proprietary process before use. Teniposide is a semisynthetic derivative of podophyllotoxin. The chemical name for teniposide is 4′-demethylepipodophyllotoxin 9-[4,6-O-(R)-2-thenylidene-β-D-glucopyranoside]. Teniposide differs from etoposide, another podophyllotoxin derivative, by the substitution of a thenylidene group on the glucopyranoside ring. 1 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Teniposide has the following structural formula: structural formula Teniposide is a white to off-white crystalline powder with the empirical formula C32H32O13S and a molecular weight of 656.66. It is a lipophilic compound with a partition coefficient value (octanol/water) of approximately 100. Teniposide is insoluble in water and ether. It is slightly soluble in methanol and very soluble in acetone and dimethylformamide. CLINICAL PHARMACOLOGY Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G2 phase of the cell cycle, thus preventing cells from entering mitosis. Teniposide causes dose-dependent single- and double-stranded breaks in DNA and DNA- protein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. Teniposide has a broad spectrum of in vivo antitumor activity against murine tumors, including hematologic malignancies and various solid tumors. Notably, teniposide is active against sublines of certain murine leukemias with acquired resistance to cisplatin, doxorubicin, amsacrine, daunorubicin, mitoxantrone, or vincristine. Plasma drug levels declined biexponentially following intravenous infusion (155 mg/m2 over 1 to 2.5 hours) of VUMON given to 8 children (4-11 years old) with newly diagnosed acute lymphoblastic leukemia (ALL). The observed average pharmacokinetic parameters and 2 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda associated coefficients of variation (CV%) based on a two-compartmental model analysis of the data are as follows: Parameter Mean CV% Total body clearance (mL/min/m2) 10.3 25 Volume at steady-state (L/m2) 3.1 30 Terminal half-life (hours) 5.0 44 Volume of central compartment (L/m2) 1.5 36 Rate constant, central to peripheral (1/hours) 0.47 62 Rate constant, peripheral to central (1/hours) 0.42 37 There appears to be some association between an increase in serum alkaline phosphatase or gamma glutamyl-transpeptidase and a decrease in plasma clearance of teniposide. Therefore, caution should be exercised if VUMON is to be administered to patients with hepatic dysfunction. In adults, at doses of 100 to 333 mg/m2/day, plasma levels increased linearly with dose. Drug accumulation in adult patients did not occur after daily administration of VUMON for 3 days. In pediatric patients, maximum plasma concentrations (Cmax) after infusions of 137 to 203 mg/m2 over a period of 1 to 2 hours exceeded 40 mcg/mL; by 20 to 24 hours after infusion plasma levels were generally <2 mcg/mL. Renal clearance of parent teniposide accounts for about 10% of total body clearance. In adults, after intravenous administration of 10 mg/kg or 67 mg/m2 of tritium-labeled teniposide, 44% of the radiolabel was recovered in urine (parent drug and metabolites) within 120 hours after dosing. From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. Mean steady-state volumes of distribution range from 8 to 44 L/m2 for adults and 3 to 11 L/m2 for children. The blood-brain barrier appears to limit diffusion of teniposide into the brain, although in a study in patients with brain tumors, CSF levels of teniposide were higher than CSF levels reported in other studies of patients who did not have brain tumors. Teniposide is highly protein bound. In vitro plasma protein binding of teniposide is >99%. The high affinity of teniposide for plasma proteins may be an important factor in limiting distribution of drug within the body. Steady-state volume of distribution of the drug increases with a decrease in plasma albumin levels. Therefore, careful monitoring of children with 3 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hypoalbuminemia is indicated during therapy. Levels of teniposide in saliva, CSF, and malignant ascites fluid are low relative to simultaneously measured plasma levels. The pharmacokinetic characteristics of teniposide differ from those of etoposide, another podophyllotoxin. Teniposide is more extensively bound to plasma proteins and its cellular uptake is greater. Teniposide also has a lower systemic clearance, a longer elimination half-life, and is excreted in the urine as parent drug to a lesser extent than etoposide. In a study at St. Jude Children’s Research Hospital (SJCRH), 9 children with acute lymphocytic leukemia (ALL) failing induction therapy with a cytarabine-containing regimen, were treated with VUMON plus cytarabine. Three of these patients were induced into complete remission with durations of remission of 30 weeks, 59 weeks, and 13 years. In another study at SJCRH, 16 children with ALL refractory to vincristine/prednisone-containing regimens were treated with VUMON plus vincristine and prednisone. Three of these patients were induced into complete remission with durations of remission of 5.5, 37, and 73 weeks. In these 2 studies, patients served as their own control based on the premise that long-term complete remissions could not be achieved by re-treatment with drugs to which they had previously failed to respond. INDICATIONS AND USAGE VUMON (teniposide injection), in combination with other approved anticancer agents, is indicated for induction therapy in patients with refractory childhood acute lymphoblastic leukemia. CONTRAINDICATIONS VUMON is generally contraindicated in patients who have demonstrated a previous hypersensitivity to teniposide and/or Cremophor® EL (polyoxyethylated castor oil). WARNINGS VUMON is a potent drug and should be used only by physicians experienced in the administration of cancer chemotherapeutic drugs. Blood counts, as well as renal and hepatic function tests, should be carefully monitored prior to and during therapy. Patients being treated with VUMON (teniposide injection) should be observed frequently for myelosuppression both during and after therapy. Dose-limiting bone marrow suppression is the most significant toxicity associated with VUMON therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of VUMON: 4 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hemoglobin, white blood cell count and differential, and platelet count. If necessary, repeat bone marrow examination should be performed prior to the decision to continue therapy in the setting of severe myelosuppression. Physicians should be aware of the possible occurrence of a hypersensitivity reaction variably manifested by chills, fever, urticaria, tachycardia, bronchospasm, dyspnea, hypertension or hypotension, rash, and facial flushing. This reaction may occur with the first dose of VUMON and may be life threatening if not treated promptly with antihistamines, corticosteroids, epinephrine, intravenous fluids, and other supportive measures as clinically indicated. The exact cause of these reactions is unknown. They may be due to the Cremophor® EL (polyoxyethylated castor oil) component of the vehicle or to teniposide itself. Patients who have experienced prior hypersensitivity reactions to VUMON are at risk for recurrence of symptoms and should only be re-treated with VUMON if the antileukemic benefit already demonstrated clearly outweighs the risk of a probable hypersensitivity reaction for that patient. When a decision is made to re-treat a patient with VUMON in spite of an earlier hypersensitivity reaction, the patient should be pretreated with corticosteroids and antihistamines and receive careful clinical observation during and after VUMON infusion. In the clinical experience with VUMON at SJCRH and the National Cancer Institute (NCI), re-treatment of patients with prior hypersensitivity reactions has been accomplished using measures described above. To date, there is no evidence to suggest cross-sensitization between VUMON and VePesid®. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving VUMON combination therapy for a non-leukemic malignancy. (See ADVERSE REACTIONS.) Patients receiving VUMON treatment should be under continuous observation for at least the first 60 minutes following the start of the infusion and at frequent intervals thereafter. If symptoms or signs of anaphylaxis occur, the infusion should be stopped immediately, followed by the administration of epinephrine, corticosteroids, antihistamines, pressor agents, or volume expanders at the discretion of the physician. An aqueous solution of epinephrine 1:1000 and a source of oxygen should be available at the bedside. For parenteral administration, VUMON should be given only by slow intravenous infusion (lasting at least 30 to 60 minutes) since hypotension has been reported as a possible side effect of rapid intravenous injection, perhaps due to a direct effect of Cremophor® EL. If clinically significant hypotension develops, the VUMON infusion should be discontinued. The blood pressure usually normalizes within hours in response to cessation of the infusion and 5 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration of fluids or other supportive therapy as appropriate. If the infusion is restarted, a slower administration rate should be used and the patient should be carefully monitored. Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients receiving investigational infusions of high-dose VUMON who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the VUMON formulation may place patients receiving higher than recommended doses of VUMON at risk for central nervous system depression. Pregnancy Pregnancy Category D VUMON may cause fetal harm when administered to a pregnant woman. VUMON has been shown to be teratogenic and embryotoxic in laboratory animals. In pregnant rats, intravenous administration of VUMON, 0.1 to 3 mg/kg (0.6-18 mg/m2), every second day from day 6 to day 16 post coitum caused dose-related embryotoxicity and teratogenicity. Major anomalies included spinal and rib defects, deformed extremities, anophthalmia, and celosomia. There are no adequate and well-controlled studies in pregnant women. If VUMON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with VUMON. Male Fertility In animal studies, VUMON caused a decrease in sperm count and genetic damage to sperm. No studies have been done to demonstrate the effect of these changes on human sperm and male fertility. Young men of reproductive age should be advised of the possibility that VUMON treatment may compromise their ability to father a child and that there is some possibility for birth defects if they do. They should be counseled on the possibility of storing sperm for future artificial insemination. PRECAUTIONS General In all instances where the use of VUMON is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be 6 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of VUMON therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity. VUMON must be administered as an intravenous infusion. Care should be taken to ensure that the intravenous catheter or needle is in the proper position and functional prior to infusion. Improper administration of VUMON may result in extravasation causing local tissue necrosis and/or thrombophlebitis. In some instances, occlusion of central venous access devices has occurred during 24-hour infusion of VUMON at a concentration of 0.1 to 0.2 mg/mL. Frequent observation during these infusions is necessary to minimize this risk. Laboratory Tests Periodic complete blood counts and assessments of renal and hepatic function should be done during the course of VUMON treatment. They should be performed prior to therapy and at clinically appropriate intervals during and after therapy. There should be at least one determination of hematologic status prior to therapy with VUMON. Drug Interactions In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate, and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. Carcinogenesis, Mutagenesis, Impairment of Fertility Children at SJCRH with ALL in remission who received maintenance therapy with VUMON at weekly or twice weekly doses (plus other chemotherapeutic agents), had a relative risk of developing secondary acute nonlymphocytic leukemia (ANLL) approximately 12 times that of patients treated according to other less intensive schedules. Reference ID: 3029513 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A short course of VUMON for remission-induction and/or consolidation therapy was not associated with an increased risk of secondary ANLL, but the number of patients assessed was small. The potential benefit from VUMON must be weighed on a case by case basis against the potential risk of the induction of a secondary leukemia. The carcinogenicity of teniposide has not been studied in laboratory animals. Compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic and teniposide should be considered a potential carcinogen in humans. Teniposide has been shown to be mutagenic in various bacterial and mammalian genetic toxicity tests. These include positive mutagenic effects in the Ames/Salmonella and B. subtilis bacterial mutagenicity assays. Teniposide caused gene mutations in both Chinese hamster ovary cells and mouse lymphoma cells and DNA damage as measured by alkaline elution in human lung carcinoma derived cell lines. In addition, teniposide induced aberrations in chromosome structure in primary cultures of human lymphocytes in vitro and in L5178y/TK +/- mouse lymphoma cells in vitro. Chromosome aberrations were observed in vivo in the embryonic tissue of pregnant Swiss albino mice treated with teniposide. Teniposide also caused a dose-related increase in sister chromatid exchanges in Chinese hamster ovary cells, and it has been shown to be embryotoxic and teratogenic in rats receiving teniposide during organogenesis. Treatment of pregnant rats intravenously with doses between 1.0 and 3.0 mg/kg/day on alternate days from day 6 to 16 post coitum caused retardation of embryonic development, prenatal mortality, and fetal abnormalities. Pregnancy Pregnancy Category D See WARNINGS. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of VUMON therapy to the mother. Pediatric Use Adverse events were evaluated in 7 studies involving 303 patients (age range 0.5 months to 20 years) who received VUMON as a single agent (see ADVERSE REACTIONS). No association between any particular age group and adverse effects was reported in any of these investigations. Reference ID: 3029513 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients with Down Syndrome Patients with both Down syndrome and leukemia may be especially sensitive to myelosuppressive chemotherapy, therefore, initial dosing with VUMON should be reduced in these patients. It is suggested that the first course of VUMON should be given at half the usual dose. Subsequent courses may be administered at higher dosages depending on the degree of myelosuppression and mucositis encountered in earlier courses in an individual patient. ADVERSE REACTIONS The table below presents the incidences of adverse reactions derived from an analysis of data contained within literature reports of 7 studies involving 303 pediatric patients in which VUMON was administered by injection as a single agent in a variety of doses and schedules for a variety of hematologic malignancies and solid tumors. The total number of patients evaluable for a given event was not 303 since the individual studies did not address the occurrence of each event listed. Five of these 7 studies assessed VUMON activity in hematologic malignancies, such as leukemia. Thus, many of these patients had abnormal hematologic status at start of therapy with VUMON and were expected to develop significant myelosuppression as an endpoint of treatment. Single-Agent VUMON Summary of Toxicity for All Evaluable Pediatric Patients Incidence in Toxicity Evaluable Patients (%) Hematologic Toxicity Myelosuppression, nonspecified 75 Leukopenia (<3,000 WBC/mcL) 89 Neutropenia (<2,000 ANC/mcL) 95 Thrombocytopenia (<100,000 plt/mcL) 85 Anemia 88 Non-Hematologic Toxicity Mucositis 76 Diarrhea 33 Nausea/vomiting 29 Infection 12 Alopecia 9 Bleeding 5 Hypersensitivity reactions 5 Rash 3 Fever 3 Hypotension/Cardiovascular 2 9 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Single-Agent VUMON Summary of Toxicity for All Evaluable Pediatric Patients Incidence in Toxicity Evaluable Patients (%) Neurotoxicity <1 Hepatic dysfunction <1 Renal dysfunction <1 Metabolic abnormalities <1 Hematologic Toxicity VUMON, when used with other chemotherapeutic agents for the treatment of ALL, results in severe myelosuppression. Sepsis, sometimes fatal, may be a consequence of severe myelosuppression. Early onset of profound myelosuppression with delayed recovery can be expected when using the doses and schedules of VUMON necessary for treatment of refractory ALL, since bone marrow hypoplasia is a desired endpoint of therapy. The occurrence of acute non-lymphocytic leukemia (ANLL), with or without a preleukemic phase, has been reported in patients treated with VUMON in combination with other antineoplastic agents. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.) Gastrointestinal Toxicity Nausea and vomiting are the most common gastrointestinal toxicities, having occurred in 29% of evaluable pediatric patients. The severity of this nausea and vomiting is generally mild to moderate. Hypotension Transient hypotension following rapid intravenous administration has been reported in 2% of evaluable pediatric patients. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving VUMON combination therapy for a non-leukemic malignancy. No other cardiac toxicity or electrocardiographic changes have been documented. No delayed hypotension has been noted. Allergic Reactions Hypersensitivity reactions characterized by chills, fever, tachycardia, flushing, bronchospasm, dyspnea, rash, and blood pressure changes (hypertension or hypotension) have been reported to occur in approximately 5% of evaluable pediatric patients receiving intravenous VUMON. The 10 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda incidence of hypersensitivity reactions to VUMON appears to be increased in patients with brain tumors and in patients with neuroblastoma. Central Nervous System Neurotoxicity has been reported, including severe cases of neuropathy, in patients receiving vincristine sulfate and VUMON concomitantly. Acute central nervous system depression and hypotension have been observed in patients receiving investigational infusions of high-dose VUMON who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the VUMON formulation may place patients receiving higher than recommended doses of VUMON at risk for central nervous system depression. Alopecia Alopecia, sometimes progressing to total baldness, was observed in 9% of evaluable pediatric patients who received VUMON as single-agent therapy. It was usually reversible. Other Adverse Reactions The following adverse reactions have been reported: headache, confusion, and asthenia. Headache and confusion were associated with hypersensitivity reactions. OVERDOSAGE Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients who were receiving higher than recommended doses of VUMON, and who were also pretreated with antiemetic drugs. There is no known antidote for VUMON overdosage. The anticipated complications of overdosage are secondary to bone marrow suppression. Treatment should consist of supportive care, including blood products and antibiotics as indicated. DOSAGE AND ADMINISTRATION NOTE: Contact of undiluted VUMON with plastic equipment or devices used to prepare solutions for infusion may result in softening or cracking and possible drug product leakage. This effect has not been reported with diluted solutions of VUMON. 11 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In order to prevent extraction of the plasticizer DEHP [di(2-ethylhexyl) phthalate], solutions of VUMON should be prepared in non-DEHP containing LVP containers such as glass or polyolefin plastic bags or containers. VUMON solutions should be administered with non-DEHP containing intravenous administration sets. In one study, childhood ALL patients failing induction therapy with a cytarabine-containing regimen were treated with the combination of VUMON 165 mg/m2 and cytarabine 300 mg/m2 intravenously, twice weekly for 8 to 9 doses. In another study, patients with childhood ALL refractory to vincristine/prednisone-containing regimens were treated with the combination of VUMON 250 mg/m2 and vincristine 1.5 mg/m2 intravenously, weekly for 4 to 8 weeks and prednisone 40 mg/m2 orally for 28 days. Adequate data in patients with hepatic insufficiency and/or renal insufficiency are lacking, but dose adjustments may be necessary for patients with significant renal or hepatic impairment. Preparation and Administration Precautions Caution should be exercised in handling and preparing the solution of VUMON. Several guidelines on proper handling and disposal of anticancer drugs have been published.1–4 Skin reactions associated with accidental exposure to VUMON may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling ampules containing VUMON. If VUMON solution contacts the skin, immediately wash the skin thoroughly with soap and water. If VUMON contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below. Preparation for Intravenous Administration VUMON must be diluted with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, to give final teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, or 1.0 mg/mL. Solutions prepared in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP at teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, or 0.4 mg/mL are stable at room temperature for up to 24 hours after preparation. VUMON solutions prepared at a final teniposide concentration of 1.0 mg/mL should be administered within 4 hours of preparation to reduce the potential for precipitation. Refrigeration of VUMON solutions is not recommended. Stability and use times are identical in glass and plastic parenteral solution containers. Reference ID: 3029513 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Although solutions are chemically stable under the conditions indicated, precipitation of teniposide may occur at the recommended concentrations, especially if the diluted solution is subjected to more agitation than is recommended to prepare the drug solution for parenteral administration. In addition, storage time prior to administration should be minimized and care should be taken to avoid contact of the diluted solution with other drugs or fluids. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Precipitation has been reported during 24-hour infusions of VUMON diluted to teniposide concentrations of 0.1 to 0.2 mg/mL, resulting in occlusion of central venous access catheters in several patients. Heparin solution can cause precipitation of teniposide, therefore, the administration apparatus should be flushed thoroughly with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP before and after administration of VUMON. Hypotension has been reported following rapid intravenous administration; it is recommended that the VUMON solution be administered over at least a 30- to 60-minute period. VUMON should not be given by rapid intravenous injection. In a 24-hour study under simulated conditions of actual use of the product relative to dilution strength, diluent and administration rates, dilutions at 0.1 to 1.0 mg/mL were chemically stable for at least 24 hours. Data collected for the presence of the extractable DEHP [di(2-ethylhexyl) phthalate] from PVC containers show that levels increased with time and concentration of the solutions. The data appeared similar for 0.9% Sodium Chloride Injection, USP, and 5% Dextrose Injection, USP. Consequently, the use of PVC containers is not recommended. Similarly, the use of non-DEHP intravenous administration sets is recommended. Lipid administration sets or low DEHP-containing nitroglycerin sets will keep patient’s exposure to DEHP at low levels and are suitable for use. The diluted solutions are chemically and physically compatible with the recommended intravenous administration sets and LVP containers for up to 24 hours at ambient room temperature and lighting conditions. Because of the potential for precipitation, compatibility with other drugs, infusion materials, or intravenous pumps cannot be assured. Stability Unopened ampules of VUMON are stable until the date indicated on the package when stored under refrigeration (2°-8°C) in the original package. Freezing does not adversely affect the product. Reference ID: 3029513 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED VUMON® (teniposide injection) NDC 0015-3075-19 50 mg/5 mL sterile, clear, colorless glass ampules individually packaged in a carton. Storage Store the unopened ampules under refrigeration (2°-8°C). Retain in original package to protect from light. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004 165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html. 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193. 4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society. VePesid® is the registered trademark of Bristol-Myers Squibb Company. Manufactured for: Bristol-Myers Squibb Company Princeton, NJ 08543 USA Made in Italy Rev September 2011 14 Reference ID: 3029513 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:46.114961	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020119s010s011lbl.pdf', 'application_number': 20119, 'submission_type': 'SUPPL ', 'submission_number': 11}
12,227	DESCRIPTION Triamcinolone acetonide, the active ingredient of AllerNaze, is a corticosteroid with the chemical name, 9α-Fluoro-11β,16α, 17, 21 tetrahydroxypregna-1,4-diene-3, 20-dione cyclic 16, 17-acetal with acetone (C24 H31 FO6 ). Its structural formula is: Structural Formula Triamcinolone acetonide, USP, is a white crystalline powder, with a molecular weight of 434.51. It, is practically insoluble in water, and sparingly soluble in dehydrated alcohol, in chloroform and in methanol. It has a melting point temperature range between 292° and 294°C. AllerNaze is a metered-dose manual spray pump in an amber polyethylene terephthalate (PET) bottle with 0.05% w/v triamcinolone acetonide in a solution containing citric acid, edetate disodium, polyethylene glycol 3350, propylene glycol, purified water, sodium citrate, and 0.01% benzalkonium chloride as a preservative. AllerNaze pH is 5.3. After initial priming (three sprays) of the AllerNaze metered pump delivery system, each spray will deliver 50 mcg of triamcinolone acetonide . If the pump was not used for more than 14 days, reprime with 3 sprays or until a fine mist is observed. Each 15 mL bottle contains 7.5 mg of triamcinolone acetonide to deliver 120 metered sprays. After 120 sprays, the amount of triamcinolone acetonide delivered per spray may not be consistent and the bottle should be discarded. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Triamcinolone acetonide is a more potent derivative of triamcinolone. Triamcinolone acetonide is approximately eight times more potent than prednisone in animal models of inflammation. The clinical significance of this is unclear. Although the precise mechanism of corticosteroid antiallergic action is unknown, corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g. mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g. histamines, eicosanoids, leukotrienes, and cytokines) involved in inflammation. Pharmacokinetics Absorption: The pharmacokinetics of triamcinolone acetonide solution was evaluated in a single-dose study conducted in 24 patients with perennial allergic rhinitis. Following a single intranasal dose of 400 mcg of triamcinolone acetonide (twice the recommended starting dose of triamcinolone acetonide solution), the mean C max of the drug was 1.12 ng/mL (SD = 0.38) with a median T max of 0.5 hours (range: 0.08 - 1.0). A pharmacokinetic study to demonstrate dose proportionality was conducted in patients with perennial allergic rhinitis. The C max and AUC of the 200 and 400 mcg doses increased less than proportionally when compared to the 100 mcg dose. Following multiple dosing (100 or 200 or 400 mcg QD for 7 days), there was no evidence of drug accumulation. Distribution: The volume of distribution (Vd) reported was 99.5 L (SD = 27.5). Metabolism : In animal studies using rats and dogs, three metabolites of triamcinolone acetonide have been identified. They are 6β hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6β-hydroxytriamcinolone acetonide. All three metabolites are expected to be substantially less active than the parent compound due to (a) the dependence of anti-inflammatory activity on the presence of a 21-hydroxyl group, (b) the decreased activity observed upon 6-hydroxylation, and (c) the markedly increased water solubility favoring rapid elimination. There appeared to be some quantitative differences in the metabolites among species. No differences were detected in metabolic pattern as a function of route of administration. Elimination : After a single intranasal dose of 400 mcg of triamcinolone acetonide (twice the recommended starting dose of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda triamcinolone acetonide solution), the mean observed elimination half-life was 2.26 hours (SD=0.77). Based upon intravenous dosing of triamcinolone acetonide phosphate ester, the half-life of triamcinolone acetonide was reported to be 88 minutes. The reported clearance was 45.2 L/hour (SD=9.1) for triamcinolone acetonide. Special Populations Age : The effect of age, specifically in geriatric and pediatric patients, on the pharmacokinetics of triamcinolone acetonide has not been studied. Gender : Gender did not significantly influence the pharmacokinetics of triamcinolone acetonide solution. Race : The effect of race on the pharmacokinetics of triamcinolone acetonide solution has not been studied. Renal/Hepatic Insufficiency : No specific pharmacokinetic studies have been conducted in renally or hepatically impaired subjects. Drug-Drug Interactions : No specific drug-drug interactions have been investigated. Pharmacodynamics A small (approximately 5 to 7 patients per treatment group), parallel trial was conducted to assess the effect of triamcinolone acetonide solution on the Hypothalamic-Pituitary-Adrenal (HPA) axis. Patients with allergic rhinitis were treated for six weeks with 400 mcg, 800 mcg, or 1600 mcg total daily doses of triamcinolone acetonide solution, 10 mg oral prednisone once daily, or placebo. Adrenal response to a six-hour cosyntropin stimulation test suggests that intranasal triamcinolone acetonide solution 400 mcg/day for six weeks did not measurably affect adrenal activity. Triamcinolone acetonide solution treatment arms using doses of 800 and 1600 mcg/day demonstrated a trend toward dose-related suppression of HPA response. However, this decrease did not reach statistical significance, whereas 10 mg daily oral prednisone did. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL TRIALS The efficacy of triamcinolone acetonide solution has been evaluated in 746 patients with seasonal or perennial allergic rhinitis who completed 8 controlled clinical trials. In total, 1187 patients have been treated with triamcinolone acetonide solution in the clinical development program. Three adequate and well controlled multi-center trials involving 541 patients with seasonal allergic rhinitis who received doses of triamcinolone acetonide solution ranging from 50 mcg to 400 mcg once daily were conducted. These trials evaluated the total nasal symptom scores that included stuffiness, rhinorrhea, itching, and sneezing. The results showed that patients who received ≥ 200 mcg daily of the active drug had statistically significant relief in the total nasal symptom score compared to those receiving placebo. In one clinical trial that examined efficacy after 2 days of 200 or 400 mcg triamcinolone acetonide solution treatment, only the 400 mcg dose showed statistically significant improvement over placebo in the nasal symptoms of seasonal allergic rhinitis. INDICATIONS AND USAGE AllerNaze is indicated for the treatment of the nasal symptoms of seasonal and perennial allergic rhinitis in adults and children 12 years of age or older. CONTRAINDICATIONS AllerNaze is contraindicated in patients with a hypersensitivity to any of its ingredients. WARNINGS The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency and, in addition, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint or muscular pain, or both, lassitude and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda conditions which require long-term corticosteroid treatment, too rapid a decrease in systemic corticosteroid may cause a severe exacerbation of their symptoms. Patients who are on immunosuppressant drugs are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in children or adults on immunosuppressant doses of corticosteroids. In children, or adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. PRECAUTIONS General: Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see PRECAUTIONS , Pediatric Use section). In clinical studies with triamcinolone acetonide nasal spray, the development of localized infections of the nose and pharynx with Candida albicans has rarely occurred. When such an infection develops it may require treatment with appropriate local therapy and discontinuance of treatment with AllerNaze. AllerNaze should be used with caution, if at all, in patients with active or quiescent tuberculous infection of the respiratory tract or in patients with untreated fungal, bacterial, or systemic viral infections or ocular herpes simplex. Because of the inhibitory effect of corticosteroids on wound healing, in patients who have experienced recent nasal septal ulcers, nasal surgery or trauma, a corticosteroid should be used with caution until healing has occurred. As with other nasally inhaled corticosteroids, nasal septal perforations have been reported in rare instances. When used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, AllerNaze should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. Systemic Availability and HPA Axis Suppression: Triamcinolone acetonide administered intranasally as triamcinolone acetonide solution has been shown to be absorbed into the systemic circulation in humans. The bioavailability of triamcinolone acetonide when administered as a solution in triamcinolone acetonide solution is approximately 5-fold greater than when administered as a CFC This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda aerosol suspension formulation. While triamcinolone acetonide solution administered to 5 patients with allergic rhinitis at 400 mcg/day for 42 days did not measurably affect adrenal response to a six-hour cosyntropin stimulation test, the 6-hour cosyntropin test is an insensitive assessment for subtle HPA effects of corticosteroids. Doses of 800 and 1600 mcg/day triamcinolone acetonide solution did demonstrate a trend toward dose-related suppression of the HPA response. However, this decrease did not reach statistical significance, whereas 10 mg daily oral prednisone did. (see Clinical Pharmacology, Pharmacodynamics ) INFORMATION FOR PATIENTS: Patients being treated with AllerNaze should receive the following information and instructions. Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to obtain medical advice. Patients should use AllerNaze at regular intervals since its effectiveness depends on its regular use. (See DOSAGE AND ADMINISTRATION ) An improvement in some patient symptoms may be seen within the first two days of treatment, and generally, it takes one week of treatment to reach maximum benefit. Initial assessment for response should be made during this time frame and periodically until the patient’s symptoms are stabilized. The patient should take the medication as directed and should not exceed the prescribed dosage. The patient should contact the physician if symptoms do not improve after three weeks, or if the condition worsens. Patients who experience recurrent episodes of epistaxis (nose bleeds) or nasal septum discomfort while taking this medication should contact their physician. Transient nasal irritation and/or burning or stinging may occur upon instillation with this product. Spraying triamcinolone acetonide directly into the eyes or onto the nasal septum should be avoided. For the proper use of this unit and to attain maximum improvement, the patient should read and follow the accompanying patient instructions carefully. The bottle should be discarded after 120 sprays following initial priming since the amount of triamcinolone acetonide delivered thereafter per spray may not be consistent. Do not transfer any remaining solution to another bottle. CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY: In two-year mouse and Sprague-Dawley rat studies, triamcinolone acetonide did not increase the incidence of tumors at oral doses up to 1 and 3 mcg/kg, respectively (less than the maximum recommended daily intranasal dose on a mcg/m 2 basis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Triamcinolone acetonide has not been found to be mutagenic in Salmonella/mammalian-microsome reverse mutation assay (Ames test) or the chromosomal aberration test in the Chinese Hamster Ovary Cells. Triamcinolone acetonide did not impair fertility in Sprague-Dawley rats given oral doses up to 15 mcg/kg (less than the maximum recommended daily intranasal dose on a mcg/m 2 basis However, triamcinolone acetonide caused increased fetal resorptions and stillbirths and decreased pup weight and survival at 5 mcg/kg (less than the maximum recommended daily intranasal dose on a mcg/m 2 basis). These effects were not produced at 1 mcg/kg (less than the maximum recommended daily intranasal dose on a mcg/m 2 basis PREGNANCY: Teratogenic Effects: Pregnancy Category C. Triamcinolone acetonide was teratogenic in rats, rabbits, and monkeys. In rats, triamcinolone acetonide was teratogenic at inhalation doses of 20 mcg/kg and above (approximately 7/10 of the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). In rabbits, triamcinolone acetonide was teratogenic at inhalation doses 20 mcg/kg and above (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). In monkeys, triamcinolone acetonide was teratogenic at an inhalation dose of 500 mcg/kg and above (approximately 37 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). Dose-related teratogenic effects in rats and rabbits included cleft palate, or internal hydrocephaly, or both and axial skeletal defects, whereas the effects observed in the monkey were cranial malformations. There are no adequate and well-controlled studies in pregnant women. Triamcinolone acetonide, like other corticosteroids, should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Since their introduction, experience with oral corticosteroids in pharmacologic as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. NONTERATOGENIC EFFECTS: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed. NURSING MOTHERS: It is not known whether triamcinolone acetonide is excreted in human breast milk. Because other corticosteroids are excreted in human milk, caution should be exercised when AllerNaze is administered to nursing women. PEDIATRIC USE: Safety and effectiveness in pediatric patients below the age of 12 years have not been established. Controlled This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including AllerNaze should be monitored routinely (e.g. via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including AllerNaze, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. GERIATRIC USE: Clinical studies of AllerNaze did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS In adequate, well-controlled and uncontrolled studies, 1187 patients have received triamcinolone acetonide solution. The adverse reactions summarized below, are based upon seven placebo controlled clinical trials of 2-6 weeks duration in 847 patients with seasonal or perennial allergic rhinitis (504 patients received 200 mcg or 400 mcg per day of triamcinolone acetonide solution and 343 patients received vehicle placebo). Adverse events reported by 2% or more of patients (regardless of relationship to treatment) who received triamcinolone acetonide solution 200 or 400 mcg once daily and that were more common with triamcinolone acetonide solution than with placebo are displayed in the table below. Overall, the incidence and nature of adverse events with triamcinolone acetonide solution 400 mcg was comparable to that seen with triamcinolone acetonide solution 200 mcg and with vehicle placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE EVENTS REPORTED AT A FREQUENCY OF 2% OR GREATER AND MORE COMMON AMONG PATIENTS TREATED WITH triamcinolone acetonide solution THAN PLACEBO REGARDLESS OF RELATIONSHIP TO TREATMENT ADVERSE EVENTS 200 mcg of triamcinolone acetonide once daily n = 204 400 mcg of triamcinolone acetonide once daily n = 300 Combined (200 and 400 mcg) use of triamcinolone acetonide n = 504 Vehicle Placebo n = 343 BODY AS A WHOLE Headache 51.0% 44.3% 47.0% 41.1% Back Pain 7.8% 4.7% 6.0% 3.5% RESPIRATORY SYSTEM Pharyngitis 13.7% 10.3% 11.7% 7.9% Asthma 5.4% 4.3% 4.8% 2.9% Cough Increased 2.0% 2.7% 2.4% 2.3% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIGESTIVE SYSTEM Dyspepsia 4.9% 2.7% 3.6% 2.0% Nausea 2.0% 3.0% 2.6% 0.6% Vomiting 1.5% 2.7% 2.2% 1.5% SPECIAL SENSES Taste Perversion 7.8% 5.0% 6.2% 2.9% Conjunctivitis 4.4% 1.3% 2.6% 1.5% MUSCULOSKELETAL SYSTEM Myalgia 2.5% 3.3% 3.0% 2.6% Adverse events reported by 2% or more of patients who received triamcinolone acetonide solution 200 or 400 mcg once daily and that were more common with placebo than with triamcinolone acetonide solution included: application site reaction (e.g. transient nasal burning and stinging), rhinitis, dysmenorrhea, pain (unspecified) and allergic reaction. The adverse effects related to the irritation of nasal mucous membranes (i.e. application site reaction) did not usually interfere with treatment. In the controlled and uncontrolled studies, approximately 0.3% of patients discontinued because of irritation of nasal OVERDOSAGE Like any other nasally administered corticosteroid, acute overdosing is unlikely in view of the total amount of active ingredient present. In the event that the entire contents of the bottle were administered all at once, via oral or nasal application, clinically significant adverse events would likely not result. The patient may experience some gastrointestinal upset. Chronic overdosage with any corticosteroid may result in signs or symptoms of hypercorticism (see PRECAUTIONS). mucous membranes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION The recommended starting dose of AllerNaze for most patients is 200 mcg per day given as 2 sprays (approximately 50 mcg/spray) in each nostril once a day. The maximum dose should not exceed 400 mcg per day. If the 400 mcg dose is used, it may be given either as a once a day dosage (4 sprays in each nostril) or divided into two daily doses of two sprays/nostril twice a day. The nasal spray pump must be primed before AllerNaze is used for the first time. To prime the pump, press down on the shoulder of the white nasal applicator using your forefinger and middle finger while supporting the base of the bottle with your thumb. Press down and release the pump until it sprays 3 times or until a fine mist is observed (see DIRECTIONS FOR USE). Some patients may obtain relief of symptoms sooner when started on a 400 mcg per day dose of AllerNaze than with 200 mcg per day. Onset of significant relief of nasal symptoms was seen within two days after starting treatment at 400 mcg once daily. A starting dose of 400 mcg per day may be considered in patients when starting therapy with AllerNaze in cases where a faster onset of relief is desirable. Generally, maximum relief of symptoms may take several days or up to one week to occur. After symptoms have been brought under control, patients should be titrated to the minimum effective dose to reduce the possibility of adverse effects. If relief of symptoms is not achieved after 14-21 days of AllerNaze therapy given in an adequate dose, AllerNaze should be discontinued and alternative diagnosis and therapies considered. AllerNaze is not recommended for use in persons under 12 years of age since its safety and effectiveness have not been established in this age group. DIRECTIONS FOR USE: Illustrated patient instructions for use accompany each package of AllerNaze. HOW SUPPLIED This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Each 15 mL bottle of AllerNaze (NDC 16781-117-15) contains 7.5 mg (0.50 mg/mL) of triamcinolone acetonide, USP and is fitted with a meter pump with white nasal applicator, teal blue dust cover and teal blue locking clip sealed in a foil pouch. The unit delivers 120 metered actuations and comes with a patient' instructions for use leaflet. The bottle should be discarded when the labeled number of actuations have been reached even though the bottle is not completely empty. Keep out of reach of children. Store at controlled room temperature: 20°-25°C (68°-77°F). Protect from freezing. Use AllerNaze within 2 months after opening of the protective foil pouch or before expiration date, whichever comes first. Rx only Collegium Pharmaceutical, Incorporated Cumberland, RI 02864-1788 Tel: 1-401-762-2000 www.collegiumpharma.com Revision 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda AllerNaze™ [AL-er-nāz] (triamcinolone acetonide) Nasal Spray INFORMATION FOR THE PATIENT These instructions provide a summary of important information about AllerNaze. Please read it carefully before use. Ask your doctor or pharmacist if you have any additional questions. What is AllerNaze? AllerNaze is a prescription medicine called a corticosteroid used to treat seasonal and year-round allergies in adults and children age 12 and older. When AllerNaze is sprayed in your nose, this medicine helps lessen the symptoms of sneezing, runny nose, and nasal itching associated with nasal allergies. Do not use AllerNaze if you 1. are pregnant or planning to become pregnant. 2. are breast feeding. 3. have had a reaction to triamcinolone acetonide or to any other nasal spray. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda How do I use AllerNaze? • Use AllerNaze on a regular schedule exactly as prescribed by your doctor • Do not usemore AllerNaze ™ or take it more often than your doctor tells you. It usually takes several days to one week of regular use to feel the medicine working. • Protect your eyes from the spray. • If your symptoms do not improve, or if they become worse, contact your doctor. • Do not stop taking AllerNaze™ without contacting your doctor. • AllerNaze does not relieve the red and itchy eye symptoms that some people have with allergic rhinitis. Ask your doctor for advice on treatment. • Tell your doctor if you have irritation, burning or stinging inside your nose that does not go away when using AllerNaze. • You may have nosebleeds after using AllerNaze. If so, contact your doctor right away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Patient Instructions for Use Read these instructions carefully before use. The following instructions tell you how to prepare your AllerNaze spray pump so that it is ready for your use. Open the foil pouch and remove the pump unit. See Figure A for a picture of the spray pump, the cap, and the safety clip. Figure A This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage Illustration Spray Pump Unit Priming the Pump: The pump needs to be primed before using it for the first time and then again if you have not used the spray for 2 weeks. You will prime the pump the same way each time. 1. Remove the blue plastic cap and the blue safety clip from the nasal applicator of the spray pump unit. See Figure B. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure B Usage Illustration 2. Prime the pump by holding the bottle with your thumb on the bottom and your index and middle fingers on top, on either side of the white nasal applicator See Figure C. 3. Point the bottle up and away from your eyes. Press down on either side of the white nasal applicator using your forefinger and middle finger, while supporting the base of the bottle with your thumb. 4. Press down and release the pump several times until you get 3 sprays or until a fine mist is seen. A fine mist can only be made by a rapid and firm pumping action. See Figure C. Figure C This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage Illustration Using the spray correctly: 1. Gently blow your nose to clear it before using the medication. 2. Remove the blue plastic cap and the blue safety clip from the nasal applicator. See Figure D. Figure D Usage Illustration 3. Prime the pump. See Figures A, B, and C in the “Priming the Pump” section. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4. Tilt your head backward slightly. Breathe out slowly. 5. Use a finger on your other hand to close your nostril on the side not receiving the medication. See Figure E. Usage Illustration 6. Insert spray tip into one nostril, as shown in the illustration. Do not insert too far back. Do not spray AllerNaze directly onto the nasal tissue inside your nose; aim the spray to the back of your nose. See Figure F. Figure F Usage Illustration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7. Breathe in through the nostril and while breathing in press the applicator once to release the spray. You will need to press firmly and rapidly. Breathe out through your mouth. 8. If the doctor has prescribed 2 sprays on each side, repeat Step 7 (above) in the same nostril and then switch to use the nasal spray in the other nostril. 9. Do not blow your nose for 15 minutes. 10. After use, wipe the spray bottle applicator off with a tissue and put the cap and safety clip back on to the bottle. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If your nasal passages are severely swollen, your doctor may recommend a decongestant nasal spray or nose drops for 3 or 4 days before using AllerNaze . CLEANING the nasal applicator: If the nasal applicator becomes blocked, and does not spray, remove it and allow it to soak in warm water for 10-15 minutes. Then rinse the applicator with clean warm water, allow it to air dry dry and put it back on the bottle. Do not try to unblock the applicator by inserting a pin or other sharp object. This could change the amount of medicine you spray and cause an overdose. STORING and discarding AllerNaze: • Store between 68º to 77º F (20º to 25º C). • Do not freeze. • Use AllerNaze within 2 months after opening the protective foil pouch or before the expiration date on the box or label, whichever comes first. • After using 120 sprays of AllerNaze throw the bottle away – the dose may not be accurate. Information about nasal symptoms of allergies (allergic rhinitis): Allergic rhinitis is a condition that causes swelling and increased watery fluid in the nose and nasal passages. This can result in sneezing, runny nose, itching, and difficulty in breathing through the nose. This response is caused by an allergy to pollen that comes from many types of plants including trees, grasses, and weeds. Allergic responses of this type may also be caused by mold spores, house dust mites, animal dander, and other substances. Collegium Pharmaceutical, Inc. Cumberland, RI 02864-1788 Tel: 1-401-762-2000 www.collegiumpharma.com This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:46.331088	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020120s002lbl.pdf', 'application_number': 20120, 'submission_type': 'SUPPL ', 'submission_number': 2}
12,228		custom-source	2025-02-12T13:46:46.473767	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20121-S009_FLONASE_prntlbl.pdf', 'application_number': 20121, 'submission_type': 'SUPPL ', 'submission_number': 9}
12,230	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLONASE safely and effectively. See full prescribing information for FLONASE. FLONASE (fluticasone propionate) Nasal Spray, 50 mcg FOR INTRANASAL USE Initial U.S. Approval: 1994 ---------------------------RECENT MAJOR CHANGES -------------------------- Indications and Usage (1) 01/2015 ----------------------------INDICATIONS AND USAGE --------------------------- FLONASE Nasal Spray is a corticosteroid indicated for the management of the nasal symptoms of perennial nonallergic rhinitis in adult and pediatric patients aged 4 years and older. (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------------- For intranasal use only. Recommended starting dosages: • Adults: 2 sprays per nostril once daily (200 mcg per day). (2.1) • Adolescents and children aged 4 years and older: 1 spray per nostril once daily (100 mcg per day). (2.2) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Nasal spray: 50 mcg of fluticasone propionate in each 100-mg spray. (3) -------------------------------CONTRAINDICATIONS ------------------------------ Hypersensitivity to any ingredient. (4) ----------------------- WARNINGS AND PRECAUTIONS----------------------- • Epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, and impaired wound healing. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma. (5.1) • Close monitoring for glaucoma and cataracts is warranted. (5.2) • Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, and rash) have been reported after administration of FLONASE Nasal Spray. Discontinue FLONASE Nasal Spray if such reactions occur. (5.3) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.4) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue FLONASE Nasal Spray slowly. (5.5) • Monitor growth of pediatric patients. (5.7) ------------------------------ ADVERSE REACTIONS ----------------------------- The most common adverse reactions (>3%) are headache, pharyngitis, epistaxis, nasal burning/nasal irritation, nausea/vomiting, asthma symptoms, and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS ------------------------------ Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of systemic corticosteroid effects. (7.1) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- Hepatic impairment: Monitor patients for signs of increased drug exposure. (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 01/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Adults 2.2 Adolescents and Children (Aged 4 Years and Older) 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Local Nasal Effects 5.2 Glaucoma and Cataracts 5.3 Hypersensitivity Reactions including Anaphylaxis 5.4 Immunosuppression 5.5 Hypercorticism and Adrenal Suppression 5.6 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors 5.7 Effect on Growth 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________ FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE FLONASE® Nasal Spray is indicated for the management of the nasal symptoms of perennial nonallergic rhinitis in adult and pediatric patients aged 4 years and older. 2 DOSAGE AND ADMINISTRATION Administer FLONASE Nasal Spray by the intranasal route only. Prime FLONASE Nasal Spray before using for the first time or after a period of non-use (1 week or more) by shaking the contents well and releasing 6 sprays into the air away from the face. Shake FLONASE Nasal Spray gently before each use. Patients should use FLONASE Nasal Spray at regular intervals since its effectiveness depends on its regular use. Maximum effect may take several days and individual patients will experience a variable time to onset and different degree of symptom relief. 2.1 Adults The recommended starting dosage in adults is 2 sprays (50 mcg of fluticasone propionate each) in each nostril once daily (total daily dose, 200 mcg). The same total daily dose, 1 spray in each nostril administered twice daily (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, patients may be able to reduce their dose to 1 spray in each nostril once daily for maintenance therapy. Maximum total daily doses should not exceed 2 sprays in each nostril (total dose, 200 mcg/day). There is no evidence that exceeding the recommended dose is more effective. 2.2 Adolescents and Children (Aged 4 Years and Older) The recommended starting dosage in adolescents and children, aged 4 years and older is 1 spray in each nostril once daily (total daily dose, 100 mcg). Patients not adequately responding to 1 spray in each nostril may use 2 sprays in each nostril once daily (total daily dose, 200 mcg). Once adequate control is achieved, the dosage should be decreased to 1 spray in each nostril once daily. The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day). There is no evidence that exceeding the recommended dose is more effective. 3 DOSAGE FORMS AND STRENGTHS FLONASE Nasal Spray is a nasal spray suspension. Each 100-mg spray delivers 50 mcg of fluticasone propionate. 2 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 CONTRAINDICATIONS FLONASE Nasal Spray is contraindicated in patients with hypersensitivity to any of its ingredients [see Warnings and Precautions (5.3), Description (11)]. 5 WARNINGS AND PRECAUTIONS 5.1 Local Nasal Effects Epistaxis In clinical trials of 2 to 26 weeks’ duration, epistaxis was observed more frequently in subjects treated with FLONASE Nasal Spray than those who received placebo [see Adverse Reactions (6.1)]. Nasal Ulceration Postmarketing cases of nasal ulceration have been reported in patients treated with FLONASE Nasal Spray [see Adverse Reactions (6.2)]. Candida Infection In clinical trials with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of FLONASE Nasal Spray. Patients using FLONASE Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. Nasal Septal Perforation Postmarketing cases of nasal septal perforation have been reported in patients treated with FLONASE Nasal Spray [see Adverse Reactions (6.2)]. Impaired Wound Healing Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should avoid using FLONASE Nasal Spray until healing has occurred. 5.2 Glaucoma and Cataracts Use of intranasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. 5.3 Hypersensitivity Reactions including Anaphylaxis Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, and rash) have been reported after administration of FLONASE Nasal Spray. Discontinue FLONASE 3 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nasal Spray if such reactions occur [see Contraindications (4)]. Rarely, immediate hypersensitivity reactions may occur after the administration of FLONASE Nasal Spray. 5.4 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the complete prescribing information for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered. Intranasal corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.5 Hypercorticism and Adrenal Suppression When intranasal corticosteroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of FLONASE Nasal Spray should be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid therapy. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression). Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms. 5.6 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, nefazodone, voriconazole) with FLONASE Nasal Spray is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. 4 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.7 Effect on Growth Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients [see Use in Specific Populations (8.4)]. Monitor the growth routinely of pediatric patients receiving FLONASE Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including FLONASE Nasal Spray, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2), Use in Specific Populations (8.4)]. 6 ADVERSE REACTIONS Systemic and local corticosteroid use may result in the following: • Epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, and impaired wound healing [see Warnings and Precautions (5.1)] • Cataracts and glaucoma [see Warnings and Precautions (5.2)] • Immunosuppression [see Warnings and Precautions (5.4)] • Hypercorticism and adrenal suppression [see Warnings and Precautions (5.5)] • Effect on growth [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled US clinical trials, more than 3,300 subjects with allergic and nonallergic rhinitis received treatment with intranasal fluticasone propionate. In general, adverse reactions in clinical trials have been primarily associated with irritation of the nasal mucous membranes, and the adverse reactions were reported with approximately the same frequency by subjects treated with placebo. Less than 2% of subjects in clinical trials discontinued because of adverse reactions; this rate was similar for vehicle placebo and active comparators. The safety data described below are based on 7 placebo-controlled clinical trials in subjects with allergic rhinitis. The 7 trials included 536 subjects (57 girls and 108 boys aged 4 to 11 years, 137 female and 234 male adolescents and adults) treated with FLONASE 200 mcg once daily over 2 to 4 weeks and 2 placebo-controlled clinical trials which included 246 subjects (119 female and 127 male adolescents and adults) treated with FLONASE 200 mcg once daily over 6 months (Table 1). Also included in Table 1 are adverse reactions from 2 trials in which 167 children (45 girls and 122 boys aged 4 to 11 years) were treated with FLONASE 100 mcg once daily for 2 to 4 weeks. 5 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1. Adverse Reactions with FLONASE Nasal Spray with >3% Incidence and More Common than Placebo in Subjects ≥4 Years with Allergic Rhinitis Adverse Reaction FLONASE 100 mcg Once Daily (n = 167) % FLONASE 200 mcg Once Daily (n = 782) % Placebo (n = 758) % Headache Pharyngitis Epistaxis Nasal burning/nasal irritation Nausea/vomiting Asthma symptoms Cough 6.6 6.0 6.0 2.4 4.8 7.2 3.6 16.1 7.8 6.9 3.2 2.6 3.3 3.8 14.6 7.2 5.4 2.6 2.0 2.9 2.8 Other adverse reactions with FLONASE Nasal Spray observed with an incidence less than or equal to 3% but greater than or equal to 1% and more common than with placebo included: blood in nasal mucus, runny nose, abdominal pain, diarrhea, fever, flu-like symptoms, aches and pains, dizziness, and bronchitis. 6.2 Postmarketing Experience In addition to adverse events reported from clinical trials, the following adverse events have been identified during postapproval use of intranasal fluticasone propionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors. General Disorders and Administration Site Conditions Hypersensitivity reactions, including angioedema, skin rash, edema of the face and tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid reactions, which in rare instances were severe. Ear and Labyrinth Disorders Alteration or loss of sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice changes. Eye Disorders Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular pressure, and cataracts. 6 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cases of growth suppression have been reported for intranasal corticosteroids, including FLONASE [see Warnings and Precautions (5.7)]. 7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, nefazodone, voriconazole) with FLONASE Nasal Spray is not recommended because increased systemic corticosteroid adverse effects may occur. Ritonavir A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate products, including FLONASE, with ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Ketoconazole Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy Category C. There are no adequate and well-controlled trials with FLONASE Nasal Spray in pregnant women. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, FLONASE Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking FLONASE Nasal Spray. Mice and rats at fluticasone propionate doses approximately 1 and 4 times, respectively, the maximum recommended human daily intranasal dose (MRHDID) for adults (on a mg/m2 basis at maternal subcutaneous doses of 45 and 100 mcg/kg/day, respectively) showed fetal toxicity 7 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at doses up to 3 times the MRHDID (on a mg/m2 basis at maternal inhalation doses up to 68.7 mcg/kg/day). In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose approximately 0.3 times the MRHDID for adults (on a mg/m2 basis at a maternal subcutaneous dose of 4 mcg/kg/day). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 20 times the MRHDID for adults (on a mg/m2 basis at a maternal oral dose up to 300 mcg/kg/day). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)]. Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. Nonteratogenic Effects Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. 8.3 Nursing Mothers It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate at a dose approximately 0.4 times the MRHDID for adults on a mg/m2 basis resulted in measurable radioactivity in milk. Since there are no data from controlled trials on the use of intranasal FLONASE Nasal Spray by nursing mothers, caution should be exercised when FLONASE Nasal Spray is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of FLONASE Nasal Spray in children aged 4 years and older have been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].Six hundred fifty (650) subjects aged 4 to 11 years and 440 subjects aged 12 to 17 years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and effectiveness of FLONASE Nasal Spray in children younger than 4 years have not been established. Effects on Growth 8 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including FLONASE Nasal Spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of intranasal corticosteroids, including FLONASE Nasal Spray, each patient’s dosage should be titrated to the lowest dosage that effectively controls his/her symptoms. A 1-year placebo-controlled trial was conducted in 150 pediatric subjects (aged 3 to 9 years) to assess the effect of FLONASE Nasal Spray (single daily dose of 200 mcg) on growth velocity. From the primary population receiving FLONASE Nasal Spray (n = 56) and placebo (n = 52), the point estimate for growth velocity with FLONASE Nasal Spray was 0.14 cm/year lower than placebo (95% CI: -0.54, 0.27 cm/year). Thus, no statistically significant effect on growth was noted compared with placebo. No evidence of clinically relevant changes in HPA axis function or bone mineral density was observed as assessed by 12-hour urinary cortisol excretion and dual-energy x-ray absorptiometry, respectively. The potential for FLONASE Nasal Spray to cause growth suppression in susceptible patients or when given at higher than recommended dosages cannot be ruled out. 8.5 Geriatric Use A limited number of subjects aged 65 years and older (n = 129) or 75 years and older (n = 11) have been treated with FLONASE Nasal Spray in clinical trials. While the number of subjects is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Formal pharmacokinetic trials using FLONASE Nasal Spray have not been conducted in subjects with hepatic impairment. Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored. 9 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.7 Renal Impairment Formal pharmacokinetic trials using FLONASE Nasal Spray have not been conducted in subjects with renal impairment. 10 OVERDOSAGE Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)]. Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days was administered to healthy human volunteers. Adverse events reported with fluticasone propionate were similar to placebo, and no clinically significant abnormalities in laboratory safety tests were observed. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. Acute overdosage with this dosage form is unlikely since 1 bottle of FLONASE Nasal Spray contains approximately 8 mg of fluticasone propionate. 11 DESCRIPTION The active component of FLONASE Nasal Spray is fluticasone propionate, a corticosteroid having the chemical name S- (fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3 oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: structural formula Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. FLONASE Nasal Spray, 50 mcg is an aqueous suspension of microfine fluticasone propionate for topical administration to the nasal mucosa by means of a metering, atomizing spray pump. FLONASE Nasal Spray also contains microcrystalline cellulose and carboxymethylcellulose sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol, and has a pH between 5 and 7. After initial priming, each actuation delivers 50 mcg of fluticasone propionate in 100 mg of formulation through the nasal adapter. 10 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown. The precise mechanism through which fluticasone propionate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. In 7 trials in adults, FLONASE Nasal Spray has decreased nasal mucosal eosinophils in 66% of patients (35% for placebo) and basophils in 39% of patients (28% for placebo). The direct relationship of these findings to long-term symptom relief is not known. 12.2 Pharmacodynamics HPA Axis Effect The potential systemic effects of FLONASE Nasal Spray on the HPA axis were evaluated. FLONASE Nasal Spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. FLONASE Nasal Spray at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin. Cardiac Electrophysiology A study specifically designed to evaluate the effect of FLONASE on the QT interval has not been conducted. 12.3 Pharmacokinetics The activity of FLONASE Nasal Spray is due to the parent drug, fluticasone propionate. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Absorption Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. After intranasal treatment of patients with rhinitis for 3 weeks, fluticasone propionate 11 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda plasma concentrations were above the level of detection (50 pg/mL) only when recommended doses were exceeded and then only in occasional samples at low plasma levels. Distribution Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averaged 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin. Elimination Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. The total blood clearance of fluticasone propionate is high (average: 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. Metabolism: The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. Excretion: Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. Special Populations Fluticasone propionate nasal spray was not studied in any special populations, and no gender- specific pharmacokinetic data have been obtained. Drug Interactions Inhibitors of Cytochrome P450 3A4: Ritonavir: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor, ritonavir, is not recommended based upon a multiple-dose, crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL), respectively, after 12 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC. Ketoconazole: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. Erythromycin: In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the MRHDID in adults and approximately 10 times the MRHDID in children on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 2 times the MRHDID in adults and approximately equivalent to the MRHDID in children on a mcg/m2 basis) for 104 weeks. Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test. No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the MRHDID in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg. 14 CLINICAL STUDIES Perennial Nonallergic Rhinitis: Three randomized, double-blind, parallel-group, vehicle placebo-controlled trials were conducted in 1,191 subjects to investigate regular use of FLONASE Nasal Spray in subjects with perennial nonallergic rhinitis. These trials evaluated subject-rated total nasal symptom scores (TNSS) that included nasal obstruction, postnasal drip, rhinorrhea in subjects treated for 28 days of double-blind therapy and in 1 of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that subjects treated with FLONASE Nasal Spray (100 mcg twice daily) exhibited statistically significant decreases in TNSS compared with subjects treated with vehicle. 16 HOW SUPPLIED/STORAGE AND HANDLING FLONASE Nasal Spray, 50 mcg is supplied in an amber glass bottle fitted with a white metering atomizing pump, white nasal adapter, and green dust cover in a box of 1 (NDC 0173-0453-01) 13 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with FDA-approved Patient Labeling (see Patient Instructions for Use for proper actuation of the device). Each bottle contains a net fill weight of 16 g and will provide 120 actuations. Each actuation delivers 50 mcg of fluticasone propionate in 100 mg of formulation through the nasal adapter. The correct amount of medication in each spray cannot be assured after 120 sprays even though the bottle is not completely empty. The bottle should be discarded when the labeled number of actuations has been used. Store between 4° and 30°C (39° and 86°F). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Local Nasal Effects Inform patients that treatment with FLONASE Nasal Spray may lead to adverse reactions, which include epistaxis and nasal ulceration. Candida infection may also occur with treatment with FLONASE Nasal Spray. In addition, FLONASE Nasal Spray has been associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use FLONASE Nasal Spray until healing has occurred [see Warnings and Precautions (5.1)]. Glaucoma and Cataracts Inform patients that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Advise patients to notify their healthcare providers if a change in vision is noted while using FLONASE Nasal Spray [see Warnings and Precautions (5.2)]. Hypersensitivity Reactions, including Anaphylaxis Inform patients that hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, contact dermatitis, and rash, may occur after administration of FLONASE Nasal Spray. If such reactions occur, patients should discontinue use of FLONASE Nasal Spray [see Warnings and Precautions (5.3)]. Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and if they are exposed to consult their healthcare provider without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex [see Warnings and Precautions (5.4)]. Reduced Growth Velocity Advise parents that FLONASE Nasal Spray may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and 14 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda adolescents taking corticosteroids by any route [see Warnings and Precautions (5.7), Pediatric Use (8.4)]. Use Daily for Best Effect Inform patients that they should use FLONASE Nasal Spray on a regular basis. FLONASE Nasal Spray, like other corticosteroids, does not have an immediate effect on rhinitis symptoms. Maximum benefit may not be reached for several days. Patients should not increase the prescribed dosage but should contact their healthcare providers if symptoms do not improve or if the condition worsens. Keep Spray Out of Eyes and Mouth Inform patients to avoid spraying FLONASE Nasal Spray in their eyes and mouth. FLONASE is a registered trademark of the GSK group of companies. company logo GlaxoSmithKline Research Triangle Park, NC 27709 ©2015, the GSK group of companies. All rights reserved. FLN:XPI 15 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patient Information FLONASE® [flow′ naz] Nasal Spray, 50 mcg (fluticasone propionate) Read the Patient Information that comes with FLONASE Nasal Spray before you start using it and each time you get a refill. There may be new information. This Patient Information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is FLONASE Nasal Spray? FLONASE Nasal Spray is a prescription medicine used to treat non-allergy nasal symptoms such as runny nose, stuffy nose, sneezing, and nasal itching in adults and children aged 4 years and older. It is not known if FLONASE Nasal Spray is safe and effective in children younger than 4 years of age. Who should not use FLONASE Nasal Spray? Do not use FLONASE Nasal Spray if you are allergic to fluticasone propionate or any of the ingredients in FLONASE Nasal Spray. See “What are the ingredients in FLONASE Nasal Spray?” below for a complete list of ingredients. What should I tell my healthcare provider before using FLONASE Nasal Spray? Tell your healthcare provider about all of your health conditions, including if you: • have or have had nasal sores, nasal surgery, or nasal injury. • have eye problems, such as cataracts or glaucoma. • have an immune system problem. • are allergic to any of the ingredients in FLONASE Nasal Spray, any other medicines, or food products. See “What are the ingredients in FLONASE Nasal Spray?” below for a complete list of ingredients. • have any type of viral, bacterial, or fungal infection. • are exposed to chickenpox or measles. • have any other medical conditions. • are pregnant or planning to become pregnant. It is not known if FLONASE Nasal Spray may harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if FLONASE Nasal Spray passes into your breast milk and if it can harm your baby. 16 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. FLONASE Nasal Spray and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your healthcare provider if you take antifungal or anti-HIV medicines. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use FLONASE Nasal Spray? Read the step-by-step instructions for using FLONASE Nasal Spray at the end of this Patient Information. • FLONASE Nasal Spray is for use in your nose only. Do not spray it in your eyes or mouth. • Children should use FLONASE Nasal Spray with an adult’s help, as instructed by the child’s healthcare provider. • Use FLONASE Nasal Spray exactly as your healthcare provider tells you. Do not use FLONASE Nasal Spray more often than prescribed. • FLONASE Nasal Spray may take several days of regular use for your rhinitis symptoms to get better. If your symptoms do not improve or get worse, call your healthcare provider. • You will get the best results if you keep using FLONASE Nasal Spray regularly each day without missing a dose. After you begin to feel better, your healthcare provider may decrease your dose. Do not stop using FLONASE Nasal Spray unless your healthcare provider tells you to do so. What are the possible side effects of FLONASE Nasal Spray? FLONASE Nasal Spray may cause serious side effects, including: • nose problems. Nose problems may include: o nose bleeds. o sores (ulcers) in your nose. o a certain fungal infection in your nose, mouth, and/or throat (thrush). o hole in the cartilage of your nose (nasal septal perforation). Symptoms of nasal septal perforation may include: • crusting in the nose 17 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • nose bleeds • runny nose • whistling sound when you breathe o slow wound healing. You should not use FLONASE Nasal Spray until your nose has healed if you have a sore in your nose, have had surgery on your nose, or if your nose has been injured. • eye problems including glaucoma and cataracts. You should have regular eye exams while you use FLONASE Nasal Spray. • serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following signs of a serious allergic reaction: o rash o hives o swelling of your face, mouth, and tongue o breathing problems • weakened immune system and increased chance of getting infections (immunosuppression). Taking medicines that weaken your immune system makes you more likely to get infections and can make certain infections worse. These infections may include tuberculosis (TB), ocular herpes simplex infections, and infections caused by fungi, bacteria, viruses, and parasites. Avoid contact with people who have a contagious disease such as chickenpox or measles while using FLONASE Nasal Spray. If you come in contact with someone who has chickenpox or measles call your healthcare provider right away. Symptoms of an infection may include: o fever o feeling tired o pain o nausea o aches o vomiting o chills • lowered steroid hormone levels (adrenal insufficiency). Adrenal insufficiency happens when your adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking medicine containing an inhaled steroid (such as FLONASE Nasal Spray). Symptoms of adrenal insufficiency may include: o feeling tired o lack of energy 18 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o weakness o nausea and vomiting o low blood pressure • slowed growth in children. A child’s growth should be checked often. The most common side effects of FLONASE Nasal Spray include: • headache • nausea and vomiting • sore throat • trouble breathing • nose bleeds • cough • nose burning or itching Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the side effects with FLONASE Nasal Spray. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store FLONASE Nasal Spray? • Store FLONASE between 39°F and 86°F (4°C and 30°C). Keep FLONASE Nasal Spray and all medicines out of the reach of children. General information about the safe and effective use of FLONASE Nasal Spray. Medicines are sometimes prescribed for purposes not mentioned in a Patient Information leaflet. Do not use FLONASE Nasal Spray for a condition for which it was not prescribed. Do not give your FLONASE Nasal Spray to other people, even if they have the same condition that you have. It may harm them. This Patient Information leaflet summarizes the most important information about FLONASE Nasal Spray. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about FLONASE Nasal Spray that was written for healthcare professionals. For more information about FLONASE Nasal Spray, call 1-888-825-5249. What are the ingredients in FLONASE Nasal Spray? 19 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Active ingredient: fluticasone propionate. Inactive ingredients: microcrystalline cellulose, carboxymethylcellulose sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol. Instructions for Use FLONASE® [flow′ naz] (fluticasone propionate) Nasal Spray, 50 mcg FLONASE Nasal Spray is for use in your nose only. Read this information before you start using your FLONASE Nasal Spray. 20 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration Figure A usage illustration Figure B usage illustration before you use it for the first time and when you have not used it for a week or more. How to prime your FLONASE Nasal Spray • Shake the bottle gently and then remove the dust cover (See Figure B). • Hold the bottle as shown (See Figure C) with the nasal applicator pointing away from you and with your forefinger and middle finger on either side of the nasal applicator and your thumb underneath the bottle. • Press down and release 6 times until a fine spray appears (See Figure C). The pump is now ready for use. Figure C Using your FLONASE Nasal Spray: Step 1. Blow your nose to clear your nostrils. 21 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda u s a g e i l l u s t r at ion ep 2. Close 1 nostril. Tilt your head forward ghtly and, keeping the bottle upright, carefully sert the nasal applicator into the other nostril (See gure D). ep 3. Start to breathe in through your nose, and hile breathing in pre ss firmly and quickly down 1 me on the applicator to release the spray. To get a ll dose, use your forefinger and middle finger to ray while supporting the base of the bottle with ur thumb. Avoid spraying in your eyes. Breathe in ntly through the nostril (See Figure E). ep 4. Breathe out through your mouth. ep 5. If a second spray is required in that nostril, peat steps 2 through 4. ep 6. Repeat steps 2 through 5 in the other nostril. ep 7. Wipe the nasal applicator with a clean tissue d replace the dust cover (See Figure F). Do not use this bottle for more than the labeled number of sprays even though the bottle is not completely empty. Before you throw the bottle away, you should talk to your healthcare provider to see if a refill is needed. Do not take extra doses or stop taking FLONASE Nasal Spray without talking to your 22 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda healthcare provider. Cleaning your FLONASE Nasal Spray: Your nasal spray should be cleaned at least 1 time each week. 1. Remove the dust cover and then gently pull upwards to free the nasal applicator. 2. Wash the applicator and dust cover under warm tap water. Allow to dry at room temperature. 3. Place the applicator and dust cover back on the bottle. 4. If the nasal applicator becomes blocked, it can be removed and left to soak in warm water. Rinse the nasal applicator with cold tap water. Dry the nasal applicator and place it back on the bottle. Do not try to unblock the nasal applicator by inserting a pin or other sharp object. Storing your FLONASE Nasal Spray: • Store FLONASE Nasal Spray between 39°F and 86°F (4°C and 30°C). • Do not use your FLONASE Nasal Spray after the date shown as “EXP” on the label or box. FLONASE is a registered trademark of the GSK group of companies. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. company logo Research Triangle Park, NC 27709 ©2015, the GSK group of companies. All rights reserved. January 2015 FLN:XPIL 23 Reference ID: 3691386 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:46.771833	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020121s044lbl.pdf', 'application_number': 20121, 'submission_type': 'SUPPL ', 'submission_number': 44}
12,229	PRESCRIBING INFORMATION 1 FLONASE® 2 (fluticasone propionate) 3 Nasal Spray, 50 mcg 4 SHAKE GENTLY 5 For Intranasal Use Only. BEFORE USE. 6 DESCRIPTION 7 Fluticasone propionate, the active component of FLONASE Nasal Spray, is a synthetic 8 corticosteroid having the chemical name S-(fluoromethyl)6α,9-difluoro-11β-17-dihydroxy-16α- 9 methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical 10 structure: 11 12 13 14 Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6, and 15 the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in 16 dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. 17 FLONASE Nasal Spray, 50 mcg is an aqueous suspension of microfine fluticasone propionate 18 for topical administration to the nasal mucosa by means of a metering, atomizing spray pump. 19 FLONASE Nasal Spray also contains microcrystalline cellulose and carboxymethylcellulose 20 sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w 21 phenylethyl alcohol, and has a pH between 5 and 7. 22 It is necessary to prime the pump before first use or after a period of non-use (1 week or 23 more). After initial priming (6 actuations), each actuation delivers 50 mcg of fluticasone 24 propionate in 100 mg of formulation through the nasal adapter. Each 16-g bottle of FLONASE 25 Nasal Spray provides 120 metered sprays. After 120 metered sprays, the amount of fluticasone 26 propionate delivered per actuation may not be consistent and the unit should be discarded. 27 CLINICAL PHARMACOLOGY 28 Mechanism of Action: Fluticasone propionate is a synthetic, trifluorinated corticosteroid with 29 anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid 30 receptor system involving binding and gene expression afforded 50% responses at 1.25 and 31 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent 32 than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also 33 support its potent glucocorticoid activity. 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In preclinical studies, fluticasone propionate revealed progesterone-like activity similar to the 35 natural hormone. However, the clinical significance of these findings in relation to the low 36 plasma levels (see Pharmacokinetics) is not known. 37 The precise mechanism through which fluticasone propionate affects allergic rhinitis 38 symptoms is not known. Corticosteroids have been shown to have a wide range of effects on 39 multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) 40 and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in 41 inflammation. In 7 trials in adults, FLONASE Nasal Spray has decreased nasal mucosal 42 eosinophils in 66% (35% for placebo) of patients and basophils in 39% (28% for placebo) of 43 patients. The direct relationship of these findings to long-term symptom relief is not known. 44 FLONASE Nasal Spray, like other corticosteroids, is an agent that does not have an 45 immediate effect on allergic symptoms. A decrease in nasal symptoms has been noted in some 46 patients 12 hours after initial treatment with FLONASE Nasal Spray. Maximum benefit may not 47 be reached for several days. Similarly, when corticosteroids are discontinued, symptoms may not 48 return for several days. 49 Pharmacokinetics: Absorption: The activity of FLONASE Nasal Spray is due to the parent 50 drug, fluticasone propionate. Indirect calculations indicate that fluticasone propionate delivered 51 by the intranasal route has an absolute bioavailability averaging less than 2%. After intranasal 52 treatment of patients with allergic rhinitis for 3 weeks, fluticasone propionate plasma 53 concentrations were above the level of detection (50 pg/mL) only when recommended doses 54 were exceeded and then only in occasional samples at low plasma levels. Due to the low 55 bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via 56 other routes of administration. Studies using oral dosing of radiolabeled drug have demonstrated 57 that fluticasone propionate is highly extracted from plasma and absorption is low. Oral 58 bioavailability is negligible, and the majority of the circulating radioactivity is due to an inactive 59 metabolite. 60 Distribution: Following intravenous administration, the initial disposition phase for 61 fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. 62 The volume of distribution averaged 4.2 L/kg. 63 The percentage of fluticasone propionate bound to human plasma proteins averaged 91% with 64 no obvious concentration relationship. Fluticasone propionate is weakly and reversibly bound to 65 erythrocytes and freely equilibrates between erythrocytes and plasma. Fluticasone propionate is 66 not significantly bound to human transcortin. 67 Metabolism: The total blood clearance of fluticasone propionate is high (average, 68 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only 69 circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone 70 propionate, which is formed through the cytochrome P450 3A4 pathway. This inactive 71 metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid 72 receptor of human lung cytosol in vitro and negligible pharmacological activity in animal 73 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been 74 detected in man. 75 Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential 76 kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a 77 radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in 78 the feces as parent drug and metabolites. 79 Special Populations: Fluticasone propionate nasal spray was not studied in any special 80 populations, and no gender-specific pharmacokinetic data have been obtained. 81 Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. 82 Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor 83 ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 84 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was 85 coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate 86 concentrations following fluticasone propionate aqueous nasal spray alone were undetectable 87 (<10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax 88 averaged 11.9 pg/mL [range, 10.8 to 14.1 pg/mL] and AUC(0-τ) averaged 8.43 pg•hr/mL [range, 89 4.2 to 18.8 pg•hr/mL]). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range, 90 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, 91 after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This 92 significant increase in plasma fluticasone propionate exposure resulted in a significant decrease 93 (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC). 94 Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are 95 coadministered with fluticasone propionate In a drug interaction study, coadministration of orally 96 inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in 97 increased fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect 98 on urinary excretion of cortisol. 99 In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone 100 propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect 101 fluticasone propionate pharmacokinetics. 102 Pharmacodynamics: In a trial to evaluate the potential systemic and topical effects of 103 FLONASE Nasal Spray on allergic rhinitis symptoms, the benefits of comparable drug blood 104 levels produced by FLONASE Nasal Spray and oral fluticasone propionate were compared. The 105 doses used were 200 mcg of FLONASE Nasal Spray, the nasal spray vehicle (plus oral placebo), 106 and 5 and 10 mg of oral fluticasone propionate (plus nasal spray vehicle) per day for 14 days. 107 Plasma levels were undetectable in the majority of patients after intranasal dosing, but present at 108 low levels in the majority after oral dosing. FLONASE Nasal Spray was significantly more 109 effective in reducing symptoms of allergic rhinitis than either the oral fluticasone propionate or 110 the nasal vehicle. This trial demonstrated that the therapeutic effect of FLONASE Nasal Spray 111 can be attributed to the topical effects of fluticasone propionate. 112 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In another trial, the potential systemic effects of FLONASE Nasal Spray on the 113 hypothalamic-pituitary-adrenal (HPA) axis were also studied in allergic patients. FLONASE 114 Nasal Spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or 115 oral prednisone 7.5 or 15 mg given in the morning. FLONASE Nasal Spray at either dose for 4 116 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both doses of 117 oral prednisone significantly reduced the response to cosyntropin. 118 Clinical Trials: A total of 13 randomized, double-blind, parallel-group, multicenter, vehicle 119 placebo-controlled clinical trials were conducted in the United States in adults and pediatric 120 patients (4 years of age and older) to investigate regular use of FLONASE Nasal Spray in 121 patients with seasonal or perennial allergic rhinitis. The trials included 2,633 adults (1,439 men 122 and 1,194 women) with a mean age of 37 (range, 18 to 79 years). A total of 440 adolescents (405 123 boys and 35 girls), mean age of 14 (range, 12 to 17 years), and 500 children (325 boys and 175 124 girls), mean age of 9 (range, 4 to 11 years) were also studied. The overall racial distribution was 125 89% white, 4% black, and 7% other. These trials evaluated the total nasal symptom scores 126 (TNSS) that included rhinorrhea, nasal obstruction, sneezing, and nasal itching in known allergic 127 patients who were treated for 2 to 24 weeks. Subjects treated with FLONASE Nasal Spray 128 exhibited significantly greater decreases in TNSS than vehicle placebo-treated patients. Nasal 129 mucosal basophils and eosinophils were also reduced at the end of treatment in adult studies; 130 however, the clinical significance of this decrease is not known. 131 There were no significant differences between fluticasone propionate regimens whether 132 administered as a single daily dose of 200 mcg (two 50-mcg sprays in each nostril) or as 133 100 mcg (one 50-mcg spray in each nostril) twice daily in 6 clinical trials. A clear dose response 134 could not be identified in clinical trials. In 1 trial, 200 mcg/day was slightly more effective than 135 50 mcg/day during the first few days of treatment; thereafter, no difference was seen. 136 Two randomized, double-blind, parallel-group, multicenter, vehicle placebo-controlled 28-day 137 trials were conducted in the United States in 732 patients (243 given FLONASE) 12 years of age 138 and older to investigate “as-needed” use of FLONASE Nasal Spray (200 mcg) in patients with 139 seasonal allergic rhinitis. Patients were instructed to take the study medication only on days 140 when they thought they needed the medication for symptom control, not to exceed 2 sprays per 141 nostril on any day, and not more than once daily. “As-needed” use was prospectively defined as 142 average use of study medication no more than 75% of study days. Average use of study 143 medications was 57% to 70% of days for all treatment arms. The studies demonstrated 144 significantly greater reduction in TNSS (sum of nasal congestion, rhinorrhea, sneezing, and nasal 145 itching) with FLONASE Nasal Spray 200 mcg compared to placebo. The relative difference in 146 efficacy with as-needed use as compared to regularly administered doses was not studied. 147 Three randomized, double-blind, parallel-group, vehicle placebo-controlled trials were 148 conducted in 1,191 patients to investigate regular use of FLONASE Nasal Spray in patients with 149 perennial nonallergic rhinitis. These trials evaluated the patient-rated TNSS (nasal obstruction, 150 postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy and in 1 of the 151 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that patients 152 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treated with FLONASE Nasal Spray at a dose of 100 mcg twice daily exhibited statistically 153 significant decreases in TNSS compared with patients treated with vehicle. 154 Individualization of Dosage: Patients should use FLONASE Nasal Spray at regular intervals 155 for optimal effect. 156 Adult patients may be started on a 200-mcg once-daily regimen (two 50-mcg sprays in each 157 nostril once daily). An alternative 200-mcg/day dosage regimen can be given as 100 mcg twice 158 daily (one 50-mcg spray in each nostril twice daily). 159 Individual patients will experience a variable time to onset and different degree of symptom 160 relief. In 4 randomized, double-blind, vehicle placebo-controlled, parallel-group allergic rhinitis 161 studies and 2 studies of patients in an outdoor “park” setting (park studies), a decrease in nasal 162 symptoms in treated subjects compared to placebo was shown to occur as soon as 12 hours after 163 treatment with a 200-mcg dose of FLONASE Nasal Spray. Maximum effect may take several 164 days. Regular-use patients who have responded may be able to be maintained (after 4 to 7 days) 165 on 100 mcg/day (1 spray in each nostril once daily). 166 Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed 167 use of FLONASE Nasal Spray (not to exceed 200 mcg daily) effective for symptom control (see 168 Clinical Trials). Greater symptom control may be achieved with scheduled regular use. Efficacy 169 of as-needed use of FLONASE Nasal Spray has not been studied in pediatric patients under 12 170 years of age with seasonal allergic rhinitis, or patients with perennial allergic or nonallergic 171 rhinitis. 172 Pediatric patients (4 years of age and older) should be started with 100 mcg (1 spray in each 173 nostril once daily). Treatment with 200 mcg (2 sprays in each nostril once daily or 1 spray in 174 each nostril twice daily) should be reserved for pediatric patients not adequately responding to 175 100 mcg daily. Once adequate control is achieved, the dosage should be decreased to 100 mcg (1 176 spray in each nostril) daily. 177 Maximum total daily doses should not exceed 2 sprays in each nostril (total dose, 178 200 mcg/day). There is no evidence that exceeding the recommended dose is more effective. 179 INDICATIONS AND USAGE 180 FLONASE Nasal Spray is indicated for the management of the nasal symptoms of seasonal 181 and perennial allergic and nonallergic rhinitis in adults and pediatric patients 4 years of age and 182 older. 183 Safety and effectiveness of FLONASE Nasal Spray in children below 4 years of age have not 184 been adequately established. 185 CONTRAINDICATIONS 186 FLONASE Nasal Spray is contraindicated in patients with a hypersensitivity to any of its 187 ingredients. 188 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS 189 The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied 190 by signs of adrenal insufficiency, and in addition some patients may experience symptoms of 191 withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously 192 treated for prolonged periods with systemic corticosteroids and transferred to topical 193 corticosteroids should be carefully monitored for acute adrenal insufficiency in response to 194 stress. In those patients who have asthma or other clinical conditions requiring long-term 195 systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a 196 severe exacerbation of their symptoms. 197 The concomitant use of intranasal corticosteroids with other inhaled corticosteroids could 198 increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis. 199 A drug interaction study in healthy subjects has shown that ritonavir (a highly potent 200 cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate 201 exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL 202 PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions). During 203 postmarketing use, there have been reports of clinically significant drug interactions in patients 204 receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects 205 including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone 206 propionate and ritonavir is not recommended unless the potential benefit to the patient 207 outweighs the risk of systemic corticosteroid side effects. 208 Persons who are using drugs that suppress the immune system are more susceptible to 209 infections than healthy individuals. Chickenpox and measles, for example, can have a more 210 serious or even fatal course in susceptible children or adults using corticosteroids. In children or 211 adults who have not had these diseases or been properly immunized, particular care should be 212 taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect 213 the risk of developing a disseminated infection is not known. The contribution of the underlying 214 disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to 215 chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If 216 exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be 217 indicated. (See the respective package inserts for complete VZIG and IG prescribing 218 information.) If chickenpox develops, treatment with antiviral agents may be considered. 219 Avoid spraying in eyes. 220 PRECAUTIONS 221 General: Intranasal corticosteroids may cause a reduction in growth velocity when administered 222 to pediatric patients (see PRECAUTIONS: Pediatric Use). 223 Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the 224 administration of FLONASE Nasal Spray. Rare instances of wheezing, nasal septum perforation, 225 cataracts, glaucoma, and increased intraocular pressure have been reported following the 226 intranasal application of corticosteroids, including fluticasone propionate. 227 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism 228 and/or suppression of HPA function. 229 Although systemic effects have been minimal with recommended doses of FLONASE Nasal 230 Spray, potential risk increases with larger doses. Therefore, larger than recommended doses of 231 FLONASE Nasal Spray should be avoided. 232 When used at higher than recommended doses or in rare individuals at recommended doses, 233 systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If 234 such changes occur, the dosage of FLONASE Nasal Spray should be discontinued slowly 235 consistent with accepted procedures for discontinuing oral corticosteroid therapy. 236 In clinical studies with fluticasone propionate administered intranasally, the development of 237 localized infections of the nose and pharynx with Candida albicans has occurred only rarely. 238 When such an infection develops, it may require treatment with appropriate local therapy and 239 discontinuation of treatment with FLONASE Nasal Spray. Patients using FLONASE Nasal 240 Spray over several months or longer should be examined periodically for evidence of Candida 241 infection or other signs of adverse effects on the nasal mucosa. 242 Intranasal corticosteroids should be used with caution, if at all, in patients with active or 243 quiescent tuberculous infections of the respiratory tract; untreated local or systemic fungal or 244 bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex. 245 Because of the inhibitory effect of corticosteroids on wound healing, patients who have 246 experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal 247 corticosteroid until healing has occurred. 248 Information for Patients: Patients being treated with FLONASE Nasal Spray should receive 249 the following information and instructions. This information is intended to aid them in the safe 250 and effective use of this medication. It is not a disclosure of all possible adverse or intended 251 effects. 252 Patients should be warned to avoid exposure to chickenpox or measles and, if exposed, to 253 consult their physician without delay. 254 Patients should use FLONASE Nasal Spray at regular intervals for optimal effect. Some 255 patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of 256 200 mcg once daily effective for symptom control (see Clinical Trials). 257 A decrease in nasal symptoms may occur as soon as 12 hours after starting therapy with 258 FLONASE Nasal Spray. Results in several clinical trials indicate statistically significant 259 improvement within the first day or two of treatment; however, the full benefit of FLONASE 260 Nasal Spray may not be achieved until treatment has been administered for several days. The 261 patient should not increase the prescribed dosage but should contact the physician if symptoms 262 do not improve or if the condition worsens. 263 For the proper use of FLONASE Nasal Spray and to attain maximum improvement, the 264 patient should read and follow carefully the patient’s instructions accompanying the product. 265 Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug 266 interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown 267 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma 268 fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations 269 (see CLINICAL PHARMACOLOGY: Drug Interactions). During postmarketing use, there have 270 been reports of clinically significant drug interactions in patients receiving fluticasone propionate 271 and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and 272 adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not 273 recommended unless the potential benefit to the patient outweighs the risk of systemic 274 corticosteroid side effects. 275 In a placebo-controlled, crossover study in 8 healthy volunteers, coadministration of a single 276 dose of orally inhaled fluticasone propionate (1,000 mcg; 5 times the maximum daily intranasal 277 dose) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma 278 fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary 279 excretion of cortisol. Caution should be exercised when FLONASE Nasal Spray is 280 coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors. 281 Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluticasone propionate 282 demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 283 20 times the maximum recommended daily intranasal dose in adults and approximately 10 times 284 the maximum recommended daily intranasal dose in children on a mcg/m2 basis) for 78 weeks or 285 in rats at inhalation doses up to 57 mcg/kg (approximately 2 times the maximum recommended 286 daily intranasal dose in adults and approximately equivalent to the maximum recommended daily 287 intranasal dose in children on a mcg/m2 basis) for 104 weeks. 288 Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells 289 in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes 290 in vitro or in the mouse micronucleus test. 291 No evidence of impairment of fertility was observed in reproductive studies conducted in 292 male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the 293 maximum recommended daily intranasal dose in adults on a mcg/m2 basis). Prostate weight was 294 significantly reduced at a subcutaneous dose of 50 mcg/kg. 295 Pregnancy: Teratogenic Effects: Pregnancy Category C. Subcutaneous studies in the 296 mouse and rat at 45 and 100 mcg/kg, respectively (approximately equivalent to and 4 times the 297 maximum recommended daily intranasal dose in adults on a mcg/m2 basis, respectively) revealed 298 fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth 299 retardation, omphalocele, cleft palate, and retarded cranial ossification. 300 In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 301 4 mcg/kg (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 302 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg 303 (approximately 25 times the maximum recommended daily intranasal dose in adults on a mcg/m2 304 basis) of fluticasone propionate to the rabbit. No fluticasone propionate was detected in the 305 plasma in this study, consistent with the established low bioavailability following oral 306 administration (see CLINICAL PHARMACOLOGY). 307 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fluticasone propionate crossed the placenta following oral administration of 100 mcg/kg to 308 rats or 300 mcg/kg to rabbits (approximately 4 and 25 times, respectively, the maximum 309 recommended daily intranasal dose in adults on a mcg/m2 basis). 310 There are no adequate and well-controlled studies in pregnant women. Fluticasone propionate 311 should be used during pregnancy only if the potential benefit justifies the potential risk to the 312 fetus. 313 Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to 314 physiologic, doses suggests that rodents are more prone to teratogenic effects from 315 corticosteroids than humans. In addition, because there is a natural increase in corticosteroid 316 production during pregnancy, most women will require a lower exogenous corticosteroid dose 317 and many will not need corticosteroid treatment during pregnancy. 318 Nursing Mothers: It is not known whether fluticasone propionate is excreted in human breast 319 milk. However, other corticosteroids have been detected in human milk. Subcutaneous 320 administration to lactating rats of 10 mcg/kg of tritiated fluticasone propionate (less than the 321 maximum recommended daily intranasal dose in adults on a mcg/m2 basis) resulted in 322 measurable radioactivity in the milk. Since there are no data from controlled trials on the use of 323 intranasal fluticasone propionate by nursing mothers, caution should be exercised when 324 FLONASE Nasal Spray is administered to a nursing woman. 325 Pediatric Use: Six hundred fifty (650) patients aged 4 to 11 years and 440 patients aged 12 to 326 17 years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and 327 effectiveness of FLONASE Nasal Spray in children below 4 years of age have not been 328 established. 329 Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in 330 growth velocity in pediatric patients. This effect has been observed in the absence of laboratory 331 evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator 332 of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA 333 axis function. The long-term effects of this reduction in growth velocity associated with 334 intranasal corticosteroids, including the impact on final adult height, are unknown. The potential 335 for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has 336 not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, 337 including FLONASE Nasal Spray, should be monitored routinely (e.g., via stadiometry). The 338 potential growth effects of prolonged treatment should be weighed against the clinical benefits 339 obtained and the risks/benefits of treatment alternatives. To minimize the systemic effects of 340 intranasal corticosteroids, including FLONASE Nasal Spray, each patient should be titrated to 341 the lowest dose that effectively controls his/her symptoms. 342 A 1-year placebo-controlled clinical growth study was conducted in 150 pediatric patients 343 (ages 3 to 9 years) to assess the effect of FLONASE Nasal Spray (single daily dose of 200 mcg, 344 the maximum approved dose) on growth velocity. From the primary population of 56 patients 345 receiving FLONASE Nasal Spray and 52 receiving placebo, the point estimate for growth 346 velocity with FLONASE Nasal Spray was 0.14 cm/year lower than that noted with placebo (95% 347 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda confidence interval ranging from 0.54 cm/year lower than placebo to 0.27 cm/year higher than 348 placebo). Thus, no statistically significant effect on growth was noted compared to placebo. No 349 evidence of clinically relevant changes in HPA axis function or bone mineral density was 350 observed as assessed by 12-hour urinary cortisol excretion and dual-energy x-ray absorptiometry, 351 respectively. 352 353 The potential for FLONASE Nasal Spray to cause growth suppression in susceptible patients 354 or when given at higher doses cannot be ruled out. 355 356 Geriatric Use: A limited number of patients 65 years of age and older (n = 129) or 75 years of 357 age and older (n = 11) have been treated with FLONASE Nasal Spray in US and non-US clinical 358 trials. While the number of patients is too small to permit separate analysis of efficacy and 359 safety, the adverse reactions reported in this population were similar to those reported by 360 younger patients. 361 ADVERSE REACTIONS 362 In controlled US studies, more than 3,300 patients with seasonal allergic, perennial allergic, or 363 perennial nonallergic rhinitis received treatment with intranasal fluticasone propionate. In 364 general, adverse reactions in clinical studies have been primarily associated with irritation of the 365 nasal mucous membranes, and the adverse reactions were reported with approximately the same 366 frequency by patients treated with the vehicle itself. The complaints did not usually interfere 367 with treatment. Less than 2% of patients in clinical trials discontinued because of adverse events; 368 this rate was similar for vehicle placebo and active comparators. 369 Systemic corticosteroid side effects were not reported during controlled clinical studies up to 370 6 months’ duration with FLONASE Nasal Spray. If recommended doses are exceeded, however, 371 or if individuals are particularly sensitive or taking FLONASE Nasal Spray in conjunction with 372 administration of other corticosteroids, symptoms of hypercorticism, e.g., Cushing syndrome, 373 could occur. 374 The following incidence of common adverse reactions (>3%, where incidence in fluticasone 375 propionate-treated subjects exceeded placebo) is based upon 7 controlled clinical trials in which 376 536 patients (57 girls and 108 boys aged 4 to11 years, 137 female and 234 male adolescents and 377 adults) were treated with FLONASE Nasal Spray 200 mcg once daily over 2 to 4 weeks and 2 378 controlled clinical trials in which 246 patients (119 female and 127 male adolescents and adults) 379 were treated with FLONASE Nasal Spray 200 mcg once daily over 6 months. Also included in 380 the table are adverse events from 2 studies in which 167 children (45 girls and 122 boys aged 4 381 to11 years) were treated with FLONASE Nasal Spray 100 mcg once daily for 2 to 4 weeks. 382 383 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Overall Adverse Experiences With >3% Incidence on Fluticasone Propionate in Controlled 384 Clinical Trials With FLONASE Nasal Spray in Patients ≥4 Years With Seasonal or 385 Perennial Allergic Rhinitis 386 Adverse Experience Vehicle Placebo (n = 758) % FLONASE 100 mcg Once Daily (n = 167) % FLONASE” 200 mcg Once Daily (n = 782) % Headache 14.6 6.6 16.1 Pharyngitis 7.2 6.0 7.8 Epistaxis 5.4 6.0 6.9 Nasal burning/nasal irritation 2.6 2.4 3.2 Nausea/vomiting 2.0 4.8 2.6 Asthma symptoms 2.9 7.2 3.3 Cough 2.8 3.6 3.8 387 Other adverse events that occurred in ≤3% but ≥1% of patients and that were more common 388 with fluticasone propionate (with uncertain relationship to treatment) included: blood in nasal 389 mucus, runny nose, abdominal pain, diarrhea, fever, flu-like symptoms, aches and pains, 390 dizziness, bronchitis. 391 Observed During Clinical Practice: In addition to adverse events reported from clinical 392 trials, the following events have been identified during postapproval use of intranasal fluticasone 393 propionate in clinical practice. Because they are reported voluntarily from a population of 394 unknown size, estimates of frequency cannot be made. These events have been chosen for 395 inclusion due to either their seriousness, frequency of reporting, or causal connection to 396 fluticasone propionate or a combination of these factors. 397 General: Hypersensitivity reactions, including angioedema, skin rash, edema of the face and 398 tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid 399 reactions, which in rare instances were severe. 400 Ear, Nose, and Throat: Alteration or loss of sense of taste and/or smell and, rarely, nasal 401 septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and 402 voice changes. 403 Eye: Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular 404 pressure, and cataracts. 405 Cases of growth suppression have been reported for intranasal corticosteroids, including 406 FLONASE (see PRECAUTIONS: Pediatric Use). 407 OVERDOSAGE 408 Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS). 409 Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate 410 twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 411 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 mg have been studied in human volunteers with no acute toxic effects reported. Repeat oral 412 doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 413 14 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and 414 incidences were similar in active and placebo treatment groups. Acute overdosage with this 415 dosage form is unlikely since 1 bottle of FLONASE Nasal Spray contains approximately 8 mg of 416 fluticasone propionate. 417 The oral and subcutaneous median lethal doses in mice and rats were >1,000 mg/kg (>20,000 418 and >41,000 times, respectively, the maximum recommended daily intranasal dose in adults and 419 >10,000 and >20,000 times, respectively, the maximum recommended daily intranasal dose in 420 children on a mg/m2 basis). 421 DOSAGE AND ADMINISTRATION 422 Patients should use FLONASE Nasal Spray at regular intervals for optimal effect. 423 Adults: The recommended starting dosage in adults is 2 sprays (50 mcg of fluticasone 424 propionate each) in each nostril once daily (total daily dose, 200 mcg). The same dosage divided 425 into 100 mcg given twice daily (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, 426 patients may be able to reduce their dosage to 100 mcg (1 spray in each nostril) once daily for 427 maintenance therapy. Some patients (12 years of age and older) with seasonal allergic rhinitis 428 may find as-needed use of 200 mcg once daily effective for symptom control (see Clinical 429 Trials). Greater symptom control may be achieved with scheduled regular use. 430 Adolescents and Children (4 Years of Age and Older): Patients should be started with 431 100 mcg (1 spray in each nostril once daily). Patients not adequately responding to 100 mcg may 432 use 200 mcg (2 sprays in each nostril). Once adequate control is achieved, the dosage should be 433 decreased to 100 mcg (1 spray in each nostril) daily. 434 The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day). 435 (See Individualization of Dosage and Clinical Trials sections.) 436 FLONASE Nasal Spray is not recommended for children under 4 years of age. 437 Directions for Use: Illustrated patient’s instructions for proper use accompany each package 438 of FLONASE Nasal Spray. 439 HOW SUPPLIED 440 FLONASE Nasal Spray 50 mcg is supplied in an amber glass bottle fitted with a white 441 metering atomizing pump, white nasal adapter, and green dust cover in a box of 1 (NDC 0173- 442 0453-01) with patient’s instructions for use. Each bottle contains a net fill weight of 16 g and 443 will provide 120 actuations. Each actuation delivers 50 mcg of fluticasone propionate in 100 mg 444 of formulation through the nasal adapter. The correct amount of medication in each spray cannot 445 be assured after 120 sprays even though the bottle is not completely empty. The bottle should be 446 discarded when the labeled number of actuations has been used. 447 Store between 4° and 30°C (39° and 86°F). 448 449 450 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 451 GlaxoSmithKline 452 Research Triangle Park, NC 27709 453 454 ©Year, GlaxoSmithKline. All rights reserved. 455 456 Month Year RL- 457 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WHAT YOU SHOULD KNOW ABOUT RHINITIS Rhinitis is a word that means inflammation of the lining of the nose. If you suffer from rhinitis, your nose becomes stuffy and runny. Rhinitis can also make your nose itchy, and you may sneeze a lot. Rhinitis can be caused by allergies to pollen, animals, molds, or other materials—or it may have a nonallergic cause. WHAT YOU SHOULD KNOW ABOUT FLONASE NASAL SPRAY Your doctor has prescribed FLONASE Nasal Spray, a medicine that can help treat your rhinitis. FLONASE Nasal Spray contains fluticasone pro- pionate, which is a synthetic corticosteroid. Corticosteroids are natural substances found in the body that help fight inflammation. When you spray FLONASE into your nose, it helps to reduce the symptoms of allergic reactions and the stuffiness, runniness, itching, and sneezing that can bother you. THINGS TO REMEMBER ABOUT FLONASE NASAL SPRAY 1. Shake gently before using. 2. Use your nasal spray as directed by your doctor. The directions are on the pharmacy label. 3. Keep your nasal spray out of the reach of children. BEFORE USING YOUR NASAL SPRAY ❖If you are pregnant (or intending to become pregnant), ❖If you are breastfeeding a baby, ❖If you are allergic to FLONASE Nasal Spray or any other nasal corticosteroid, ❖If you are taking a medicine containing ritonavir (commonly used to treat HIV infection or AIDS), TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDI- CINE. In some circumstances, this medicine may not be suitable and your doctor may wish to give you a different medicine. Make sure that your doctor knows what other medicines you are taking. USING YOUR NASAL SPRAY ❖Follow the instructions shown in the rest of this leaflet. If you have any problems, tell your doctor or pharmacist. ❖It is important that you use it as directed by your doctor. The pharma- cist’s label will usually tell you what dose to take and how often. If it doesn’t, or you are not sure, ask your doctor or pharmacist. DOSAGE ❖For ADULTS, the usual starting dosage is 2 sprays in each nostril once daily. Sometimes your doctor may recommend using 1 spray in each nostril twice a day (morning and evening). You should not use more than a total of 2 sprays in each nostril daily. After you have begun to feel better, 1 spray in each nostril daily may be adequate for you. For ADOLESCENTS and CHILDREN (4 years of age and older), the usual starting dosage is 1 spray in each nostril once daily. Some- times your doctor may recommend using 2 sprays in each nostril daily. Then, after you have begun to feel better, 1 spray in each nostril daily may be adequate for you. ❖DO NOT use more of your medicine or take it more often than your doctor advises. ❖FLONASE may begin to work within 12 hours of the first dose, but it takes several days of regular use to reach its greatest effect. It is important that you use FLONASE Nasal Spray as prescribed by your doctor. Best results will be obtained by using the spray on a regular basis. If symptoms disappear, contact your doctor for further instructions. ❖If you also have itchy, watery eyes, you should tell your doctor. You may be given an additional medicine to treat your eyes. Be careful not to confuse them, particularly if the second medicine is an eye drop. ❖If you miss a dose, just take your regularly scheduled next dose when it is due. DO NOT DOUBLE the dose. HOW TO USE YOUR NASAL SPRAY Read the complete instructions carefully and use only as directed. BEFORE USING Shake the bottle gently and 1. then remove the dust cover (Figure 1). Please read this leaflet carefully before you start to take your medicine. It provides a summary of information on your medicine. For further information ask your doctor or pharmacist. FIGURE 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is necessary to prime the 2. pump into the air the first time it is used, or when you have not used it for a week or more. To prime the pump, hold the bottle as shown with the nasal applicator pointing away from you and with your forefinger and middle finger on either side of the nasal applicator and your thumb underneath the bottle. When you prime the pump for the first time, press down and release the pump 6 times. (Figure 2). The pump is now ready for use. If the pump is not used for 7 days, prime until a fine spray appears. USING THE SPRAY Blow your nose to clear 3. your nostrils. Close one nostril. Tilt your 4. head forward slightly and, keeping the bottle upright, carefully insert the nasal applicator into the other nostril (Figure 3). Start to breathe in through 5. your nose, and WHILE BREATHING IN press firmly and quickly down once on the applicator to release the spray. To get a full actuation, use your forefinger and mid- dle finger to spray while sup- porting the base of the bottle with your thumb. Avoid spray- ing in eyes. Breathe gently inwards through the nostril (Figure 4). Breathe out through 6. your mouth. If a second spray is required 7. in that nostril, repeat steps 4 through 6. Repeat steps 4 through 7 in 8. the other nostril. Wipe the nasal applicator 9. with a clean tissue and replace the dust cover (Figure 5). Do not use this bottle for 10. more than the labeled number of sprays even though the bottle is not completely empty. Before you throw the bottle away, you should consult your doctor to see if a refill is needed. Do not take extra doses or stop taking FLONASE Nasal Spray with- out consulting your doctor. CLEANING Your nasal spray should be cleaned at least once a week. To do this: 1. Remove the dust cover and then gently pull upwards to free the nasal applicator. 2. Wash the applicator and dust cover under warm tap water. Allow to dry at room temperature, then place the applicator and dust cover back on the bottle. 3. If the nasal applicator becomes blocked, it can be removed as above and left to soak in warm water. Rinse with cold tap water, dry, and refit. Do not try to unblock the nasal appli- cator by inserting a pin or other sharp object. STORING YOUR NASAL SPRAY ❖Keep your FLONASE Nasal Spray out of the reach of children. ❖Avoid spraying in eyes. ❖Store between 4° and 30°C (39° and 86°F). ❖Do not use your FLONASE Nasal Spray after the date shown as “EXP” on the label or box. REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT give this medicine to anyone else. FURTHER INFORMATION This leaflet does not contain the complete information about your medicine. If you have any questions, or are not sure about something, then you should ask your doctor or pharmacist. You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine. FIGURE 2 FIGURE 3 FIGURE 5 FIGURE 4 GlaxoSmithKline Research Triangle Park, NC 27709 ©2003, GlaxoSmithKline. All rights reserved. July 2003 RL-2019 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 PRESCRIBING INFORMATION 1 FLOVENT® 44 mcg 2 (fluticasone propionate, 44 mcg) 3 Inhalation Aerosol 4 5 FLOVENT® 110 mcg 6 (fluticasone propionate, 110 mcg) 7 Inhalation Aerosol 8 9 FLOVENT® 220 mcg 10 (fluticasone propionate, 220 mcg) 11 Inhalation Aerosol 12 13 For Oral Inhalation Only 14 DESCRIPTION 15 The active component of FLOVENT 44 mcg Inhalation Aerosol, FLOVENT 110 mcg 16 Inhalation Aerosol, and FLOVENT 220 mcg Inhalation Aerosol is fluticasone propionate, a 17 glucocorticoid having the chemical name S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α- 18 methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical 19 structure: 20 21 22 23 Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6. It is 24 practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and 25 slightly soluble in methanol and 95% ethanol. 26 FLOVENT 44 mcg Inhalation Aerosol, FLOVENT 110 mcg Inhalation Aerosol, and 27 FLOVENT 220 mcg Inhalation Aerosol are pressurized, metered-dose aerosol units intended for 28 oral inhalation only. Each unit contains a microcrystalline suspension of fluticasone propionate 29 (micronized) in a mixture of 2 chlorofluorocarbon propellants (trichlorofluoromethane and 30 dichlorodifluoromethane) with soya lecithin. Each actuation of the inhaler delivers 50, 125, or 31 250 mcg of fluticasone propionate from the valve and 44, 110, or 220 mcg, respectively, of 32 fluticasone propionate from the actuator. 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 CLINICAL PHARMACOLOGY 34 Fluticasone propionate is a synthetic, trifluorinated glucocorticoid with potent 35 anti-inflammatory activity. In vitro assays using human lung cytosol preparations have 36 established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 37 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate 38 (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of 39 budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these 40 results. 41 The precise mechanisms of glucocorticoid action in asthma are unknown. Inflammation is 42 recognized as an important component in the pathogenesis of asthma. Glucocorticoids have been 43 shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, 44 macrophages, and neutrophils) and mediator production or secretion (e.g., histamine, 45 eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These 46 anti-inflammatory actions of glucocorticoids may contribute to their efficacy in asthma. 47 Though highly effective for the treatment of asthma, glucocorticoids do not affect asthma 48 symptoms immediately. However, improvement following inhaled administration of fluticasone 49 propionate can occur within 24 hours of beginning treatment, although maximum benefit may 50 not be achieved for 1 to 2 weeks or longer after starting treatment. When glucocorticoids are 51 discontinued, asthma stability may persist for several days or longer. 52 Pharmacokinetics: Absorption: The activity of FLOVENT Inhalation Aerosol is due to the 53 parent drug, fluticasone propionate. Studies using oral dosing of labeled and unlabeled drug have 54 demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), 55 primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In 56 contrast, the majority of the fluticasone propionate delivered to the lung is systemically 57 absorbed. The systemic bioavailability of fluticasone propionate inhalation aerosol in healthy 58 volunteers averaged about 30% of the dose delivered from the actuator. 59 Peak plasma concentrations after an 880-mcg inhaled dose ranged from 0.1 to 1.0 ng/mL. 60 Distribution: Following intravenous administration, the initial disposition phase for 61 fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. 62 The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to 63 human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to 64 erythrocytes. Fluticasone propionate is not significantly bound to human transcortin. 65 Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), 66 with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite 67 detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed 68 through the cytochrome P450 3A4 pathway. This metabolite had approximately 2,000 times less 69 affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and 70 negligible pharmacological activity in animal studies. Other metabolites detected in vitro using 71 cultured human hepatoma cells have not been detected in man. 72 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Excretion: Following intravenous dosing, fluticasone propionate showed polyexponential 73 kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a 74 radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in 75 the feces as parent drug and metabolites. 76 Special Populations: Formal pharmacokinetic studies using fluticasone propionate were 77 not carried out in any special populations. In a clinical study using fluticasone propionate 78 inhalation powder, trough fluticasone propionate plasma concentrations were collected in 76 79 males and 74 females after inhaled administration of 100 and 500 mcg twice daily. Full 80 pharmacokinetic profiles were obtained from 7 female patients and 13 male patients at these 81 doses, and no overall differences in pharmacokinetic behavior were found. 82 Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. 83 Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor 84 ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 85 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was 86 coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate 87 concentrations following fluticasone propionate aqueous nasal spray alone were undetectable 88 (<10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax 89 averaged 11.9 pg/mL [range, 10.8 to 14.1 pg/mL] and AUC(0-τ) averaged 8.43 pg•hr/mL [range, 90 4.2 to 18.8 pg•hr/mL]). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range, 91 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, 92 after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This 93 significant increase in plasma fluticasone propionate exposure resulted in a significant decrease 94 (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC). 95 Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are 96 coadministered with fluticasone propionate. In a drug interaction study, coadministration of 97 orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted 98 in increased plasma fluticasone propionate exposure and reduced plasma cortisol AUC, but had 99 no effect on urinary excretion of cortisol. 100 In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone 101 propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect 102 fluticasone propionate pharmacokinetics. 103 Pharmacodynamics: To confirm that systemic absorption does not play a role in the clinical 104 response to inhaled fluticasone propionate, a double-blind clinical study comparing inhaled and 105 oral fluticasone propionate was conducted. Doses of 100 and 500 mcg twice daily of fluticasone 106 propionate inhalation powder were compared to oral fluticasone propionate, 20,000 mcg given 107 once daily, and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in 108 all 3 active groups, but the mean values were highest in the oral group. Both doses of inhaled 109 fluticasone propionate were effective in maintaining asthma stability and improving lung 110 function while oral fluticasone propionate and placebo were ineffective. This demonstrates that 111 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 the clinical effectiveness of inhaled fluticasone propionate is due to its direct local effect and not 112 to an indirect effect through systemic absorption. 113 The potential systemic effects of inhaled fluticasone propionate on the 114 hypothalamic-pituitary-adrenal (HPA) axis were also studied in patients with asthma. 115 Fluticasone propionate given by inhalation aerosol at doses of 220, 440, 660, or 880 mcg twice 116 daily was compared with placebo or oral prednisone 10 mg given once daily for 4 weeks. For 117 most patients, the ability to increase cortisol production in response to stress, as assessed by 118 6-hour cosyntropin stimulation, remained intact with inhaled fluticasone propionate treatment. 119 No patient had an abnormal response (peak less than 18 mcg/dL) after dosing with placebo or 120 220 mcg twice daily. Ten percent (10%) to 16% of patients treated with fluticasone propionate at 121 doses of 440 mcg or more twice daily had an abnormal response as compared to 29% of patients 122 treated with prednisone. 123 CLINICAL TRIALS 124 Double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,818 125 adolescent and adult patients with asthma to assess the efficacy and/or safety of FLOVENT 126 Inhalation Aerosol in the treatment of asthma. Fixed doses ranging from 22 to 880 mcg twice 127 daily were compared to placebo to provide information about appropriate dosing to cover a range 128 of asthma severity. Patients with asthma included in these studies were those not adequately 129 controlled with beta-agonists alone, those already maintained on daily inhaled corticosteroids, 130 and those requiring oral corticosteroid therapy. In all efficacy trials, at all doses, measures of 131 pulmonary function (forced expiratory volume in 1 second [FEV1] and morning peak expiratory 132 flow [AM PEF]) were statistically significantly improved as compared with placebo. 133 In 2 clinical trials of 660 patients with asthma inadequately controlled on bronchodilators 134 alone, FLOVENT Inhalation Aerosol was evaluated at doses of 44 and 88 mcg twice daily. Both 135 doses of FLOVENT Inhalation Aerosol improved asthma control significantly as compared with 136 placebo. 137 Figure 1 displays results of pulmonary function tests for the recommended starting dosage of 138 FLOVENT Inhalation Aerosol (88 mcg twice daily) and placebo from a 12-week trial in patients 139 with asthma inadequately controlled on bronchodilators alone. Because this trial used 140 predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be 141 withdrawn, pulmonary function results at Endpoint, which is the last evaluable FEV1 result and 142 includes most patients’ lung function data, are also provided. Pulmonary function improved 143 significantly with FLOVENT Inhalation Aerosol compared with placebo by the second week of 144 treatment, and this improvement was maintained over the duration of the trial. 145 146 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Figure 1. A 12-Week Clinical Trial in Patients Inadequately 147 Controlled on Bronchodilators Alone: Mean Percent Change 148 From Baseline in FEV1 Prior to AM Dose 149 150 151 152 In clinical trials of 924 patients with asthma already receiving daily inhaled corticosteroid 153 therapy (doses of at least 336 mcg/day of beclomethasone dipropionate) in addition to as-needed 154 albuterol and theophylline (46% of all patients), 22- to 440-mcg twice-daily doses of FLOVENT 155 Inhalation Aerosol were also evaluated. All doses of FLOVENT Inhalation Aerosol were 156 efficacious when compared to placebo on major endpoints including lung function and symptom 157 scores. Patients treated with FLOVENT Inhalation Aerosol were also less likely to discontinue 158 study participation due to asthma deterioration (as defined by predetermined criteria for lack of 159 efficacy including lung function and patient-recorded variables such as AM PEF, albuterol use, 160 and nighttime awakenings due to asthma). 161 Figure 2 displays results of pulmonary function from a 12-week clinical trial in patients with 162 asthma already receiving daily inhaled corticosteroid therapy (beclomethasone dipropionate 336 163 to 672 mcg/day). The mean percent change from baseline in lung function results for FLOVENT 164 Inhalation Aerosol dosages of 88, 220, and 440 mcg twice daily and placebo are shown over the 165 12-week trial. Because this trial also used predetermined criteria for lack of efficacy, which 166 caused more patients in the placebo group to be withdrawn, pulmonary function results at 167 Endpoint are included. Pulmonary function improved significantly with FLOVENT Inhalation 168 Aerosol compared with placebo by the first week of treatment, and the improvement was 169 maintained over the duration of the trial. Analysis of the endpoint results that adjusted for 170 differential withdrawal rates indicated that pulmonary function significantly improved with 171 FLOVENT Inhalation Aerosol compared with placebo treatment. Similar improvements in lung 172 function were seen in the other 2 trials in patients treated with inhaled corticosteroids at baseline. 173 174 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Figure 2. A 12-Week Clinical Trial With Patients Already 175 Receiving Inhaled Corticosteroids: Mean Percent Change 176 From Baseline in FEV1 Prior to AM Dose 177 178 179 180 In a clinical trial of 96 patients with severe asthma requiring chronic oral prednisone therapy 181 (average baseline daily prednisone dose was 10 mg), twice-daily doses of 660 and 880 mcg of 182 FLOVENT Inhalation Aerosol were evaluated. Both doses enabled a statistically significantly 183 larger percentage of patients to wean successfully from oral prednisone as compared with 184 placebo (69% of the patients on 660 mcg twice daily and 88% of the patients on 880 mcg twice 185 daily as compared with 3% of patients on placebo). Accompanying the reduction in oral 186 corticosteroid use, patients treated with FLOVENT Inhalation Aerosol had significantly 187 improved lung function and fewer asthma symptoms as compared with the placebo group. 188 189 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Figure 3. A 16-Week Clinical Trial in Patients Requiring 190 Chronic Oral Prednisone Therapy: Change in Maintenance 191 Prednisone Dose 192 193 194 195 INDICATIONS AND USAGE 196 FLOVENT Inhalation Aerosol is indicated for the maintenance treatment of asthma as 197 prophylactic therapy. It is also indicated for patients requiring oral corticosteroid therapy for 198 asthma. Many of these patients may be able to reduce or eliminate their requirement for oral 199 corticosteroids over time. 200 FLOVENT Inhalation Aerosol is NOT indicated for the relief of acute bronchospasm. 201 CONTRAINDICATIONS 202 FLOVENT Inhalation Aerosol is contraindicated in the primary treatment of status 203 asthmaticus or other acute episodes of asthma where intensive measures are required. 204 Hypersensitivity to any of the ingredients of these preparations contraindicates their use (see 205 DESCRIPTION). 206 WARNINGS 207 Particular care is needed for patients who are transferred from systemically active 208 corticosteroids to FLOVENT Inhalation Aerosol because deaths due to adrenal insufficiency 209 have occurred in patients with asthma during and after transfer from systemic corticosteroids to 210 less systemically available inhaled corticosteroids. After withdrawal from systemic 211 corticosteroids, a number of months are required for recovery of HPA function. 212 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Patients who have been previously maintained on 20 mg or more per day of prednisone (or its 213 equivalent) may be most susceptible, particularly when their systemic corticosteroids have been 214 almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs 215 and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection 216 (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although 217 FLOVENT Inhalation Aerosol may provide control of asthma symptoms during these episodes, 218 in recommended doses it supplies less than normal physiological amounts of glucocorticoid 219 systemically and does NOT provide the mineralocorticoid activity that is necessary for coping 220 with these emergencies. 221 During periods of stress or a severe asthma attack, patients who have been withdrawn from 222 systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) 223 immediately and to contact their physicians for further instruction. These patients should also be 224 instructed to carry a warning card indicating that they may need supplementary systemic 225 corticosteroids during periods of stress or a severe asthma attack. 226 A drug interaction study in healthy subjects has shown that ritonavir (a highly potent 227 cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate 228 exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL 229 PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions). During 230 postmarketing use, there have been reports of clinically significant drug interactions in patients 231 receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects 232 including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone 233 propionate and ritonavir is not recommended unless the potential benefit to the patient 234 outweighs the risk of systemic corticosteroid side effects. 235 Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid 236 use after transferring to FLOVENT Inhalation Aerosol. In a trial of 96 patients, prednisone 237 reduction was successfully accomplished by reducing the daily prednisone dose by 2.5 mg on a 238 weekly basis during transfer to inhaled fluticasone propionate. Successive reduction of 239 prednisone dose was allowed only when lung function, symptoms, and as-needed beta-agonist 240 use were better than or comparable to that seen before initiation of prednisone dose reduction. 241 Lung function (FEV1 or AM PEF), beta-agonist use, and asthma symptoms should be carefully 242 monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and 243 symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as 244 fatigue, lassitude, weakness, nausea and vomiting, and hypotension. 245 Transfer of patients from systemic corticosteroid therapy to FLOVENT Inhalation Aerosol 246 may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., 247 rhinitis, conjunctivitis, eczema, and arthritis. 248 Persons who are on drugs that suppress the immune system are more susceptible to infections 249 than healthy individuals. Chickenpox and measles, for example, can have a more serious or even 250 fatal course in susceptible children or adults on corticosteroids. In such children or adults who 251 have not had these diseases, particular care should be taken to avoid exposure. How the dose, 252 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 route, and duration of corticosteroid administration affect the risk of developing a disseminated 253 infection is not known. The contribution of the underlying disease and/or prior corticosteroid 254 treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella 255 zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with 256 pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts 257 for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with 258 antiviral agents may be considered. 259 FLOVENT Inhalation Aerosol is not to be regarded as a bronchodilator and is not indicated 260 for rapid relief of bronchospasm. 261 As with other inhaled asthma medications, bronchospasm may occur with an immediate 262 increase in wheezing after dosing. If bronchospasm occurs following dosing with FLOVENT 263 Inhalation Aerosol, it should be treated immediately with a fast-acting inhaled bronchodilator. 264 Treatment with FLOVENT Inhalation Aerosol should be discontinued and alternative therapy 265 instituted. 266 Patients should be instructed to contact their physicians immediately when episodes of asthma 267 that are not responsive to bronchodilators occur during the course of treatment with FLOVENT 268 Inhalation Aerosol. During such episodes, patients may require therapy with oral corticosteroids. 269 PRECAUTIONS 270 General: During withdrawal from oral corticosteroids, some patients may experience symptoms 271 of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and 272 depression, despite maintenance or even improvement of respiratory function. 273 Fluticasone propionate will often permit control of asthma symptoms with less suppression of 274 HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone 275 propionate is absorbed into the circulation and can be systemically active at higher doses, the 276 beneficial effects of FLOVENT Inhalation Aerosol in minimizing HPA dysfunction may be 277 expected only when recommended dosages are not exceeded and individual patients are titrated 278 to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and 279 inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment 280 with FLOVENT Inhalation Aerosol. Since individual sensitivity to effects on cortisol production 281 exists, physicians should consider this information when prescribing FLOVENT Inhalation 282 Aerosol. 283 Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated 284 with these drugs should be observed carefully for any evidence of systemic corticosteroid effects. 285 Particular care should be taken in observing patients postoperatively or during periods of stress 286 for evidence of inadequate adrenal response. 287 It is possible that systemic corticosteroid effects such as hypercorticism and adrenal 288 suppression (including adrenal crisis) may appear in a small number of patients, particularly 289 when FLOVENT Inhalation Aerosol is administered at higher than recommended doses over 290 prolonged periods of time. If such effects occur, fluticasone propionate inhalation aerosol should 291 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and 292 for management of asthma symptoms. 293 A reduction of growth velocity in children or teenagers may occur as a result of inadequate 294 control of chronic diseases such as asthma or from use of corticosteroids for treatment. 295 Physicians should closely follow the growth of adolescents taking corticosteroids by any route 296 and weigh the benefits of corticosteroid therapy and asthma control against the possibility of 297 growth suppression if an adolescent’s growth appears slowed. 298 The long-term effects of fluticasone propionate in human subjects are not fully known. In 299 particular, the effects resulting from chronic use of fluticasone propionate on developmental or 300 immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Some patients 301 have received fluticasone propionate inhalation aerosol on a continuous basis for periods of 302 3 years or longer. In clinical studies with patients treated for nearly 2 years with inhaled 303 fluticasone propionate, no apparent differences in the type or severity of adverse reactions were 304 observed after long- versus short-term treatment. 305 Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported 306 following the inhaled administration of corticosteroids, including fluticasone propionate. 307 In clinical studies with inhaled fluticasone propionate, the development of localized infections 308 of the pharynx with Candida albicans has occurred. When such an infection develops, it should 309 be treated with appropriate local or systemic (i.e., oral antifungal) therapy while remaining on 310 treatment with FLOVENT Inhalation Aerosol, but at times therapy with FLOVENT Inhalation 311 Aerosol may need to be interrupted. 312 Inhaled corticosteroids should be used with caution, if at all, in patients with active or 313 quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral 314 or parasitic infections; or ocular herpes simplex. 315 Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may 316 present with systemic eosinophilic conditions, with some patients presenting with clinical 317 features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated 318 with systemic corticosteroid therapy. These events usually, but not always, have been associated 319 with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of 320 fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with 321 other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, 322 vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy 323 presenting in their patients. A causal relationship between fluticasone propionate and these 324 underlying conditions has not been established (see ADVERSE REACTIONS). 325 Information for Patients: Patients being treated with FLOVENT Inhalation Aerosol should 326 receive the following information and instructions. This information is intended to aid them in 327 the safe and effective use of this medication. It is not a disclosure of all possible adverse or 328 intended effects. 329 Patients should use FLOVENT Inhalation Aerosol at regular intervals as directed. Results of 330 clinical trials indicated significant improvement may occur within the first day or two of 331 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 treatment; however, the full benefit may not be achieved until treatment has been administered 332 for 1 to 2 weeks or longer. The patient should not increase the prescribed dosage but should 333 contact the physician if symptoms do not improve or if the condition worsens. 334 After inhalation, rinse the mouth with water without swallowing. 335 Patients should be warned to avoid exposure to chickenpox or measles and, if they are 336 exposed, to consult the physician without delay. 337 For the proper use of FLOVENT Inhalation Aerosol and to attain maximum improvement, the 338 patient should read and follow carefully the Patient’s Instructions for Use accompanying the 339 product. 340 Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug 341 interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown 342 that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma 343 fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations 344 (see CLINICAL PHARMACOLOGY: Drug Interactions). During postmarketing use, there have 345 been reports of clinically significant drug interactions in patients receiving fluticasone propionate 346 and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and 347 adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not 348 recommended unless the potential benefit to the patient outweighs the risk of systemic 349 corticosteroid side effects. 350 In a placebo-controlled, crossover study in 8 healthy volunteers, coadministration of a single 351 dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole 352 (200 mg) to steady state resulted in increased mean plasma fluticasone propionate exposure, a 353 reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should 354 be exercised when FLOVENT Inhalation Aerosol is coadministered with ketoconazole and other 355 known potent cytochrome P450 3A4 inhibitors. 356 Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluticasone propionate 357 demonstrated no tumorigenic potential in studies of oral doses up to 1,000 mcg/kg 358 (approximately 2 times the maximum human daily inhalation dose based on mcg/m2) for 359 78 weeks in the mouse or inhalation of up to 57 mcg/kg (approximately 1/4 the maximum human 360 daily inhalation dose based on mcg/m2) for 104 weeks in the rat. 361 Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in 362 vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in 363 vitro or in the mouse micronucleus test when administered at high doses by the oral or 364 subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone 365 marrow. 366 No evidence of impairment of fertility was observed in reproductive studies conducted in rats 367 dosed subcutaneously with doses up to 50 mcg/kg (approximately 1/4 the maximum human daily 368 inhalation dose based on mcg/m2) in males and females. However, prostate weight was 369 significantly reduced in rats. 370 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Pregnancy: Teratogenic Effects: Pregnancy Category C. Subcutaneous studies in the 371 mouse and rat at 45 and 100 mcg/kg, respectively (approximately 1/10 and 1/2 the maximum 372 human daily inhalation dose based on mcg/m2, respectively), revealed fetal toxicity characteristic 373 of potent glucocorticoid compounds, including embryonic growth retardation, omphalocele, cleft 374 palate, and retarded cranial ossification. 375 In the rabbit, fetal weight reduction and cleft palate were observed following subcutaneous 376 doses of 4 mcg/kg (approximately 1/25 the maximum human daily inhalation dose based on 377 mcg/m2). However, following oral administration of up to 300 mcg/kg (approximately 3 times 378 the maximum human daily inhalation dose based on mcg/m2) of fluticasone propionate to the 379 rabbit, there were no maternal effects nor increased incidence of external, visceral, or skeletal 380 fetal defects. No fluticasone propionate was detected in the plasma in this study, consistent with 381 the established low bioavailability following oral administration (see CLINICAL 382 PHARMACOLOGY). 383 Less than 0.008% of the administered dose crossed the placenta following oral administration 384 of 100 mcg/kg to rats or 300 mcg/kg to rabbits (approximately 1/2 and 3 times the maximum 385 human daily inhalation dose based on mcg/m2, respectively). 386 There are no adequate and well-controlled studies in pregnant women. FLOVENT Inhalation 387 Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk 388 to the fetus. 389 Experience with oral glucocorticoids since their introduction in pharmacologic, as opposed to 390 physiologic, doses suggests that rodents are more prone to teratogenic effects from 391 glucocorticoids than humans. In addition, because there is a natural increase in glucocorticoid 392 production during pregnancy, most women will require a lower exogenous glucocorticoid dose 393 and many will not need glucocorticoid treatment during pregnancy. 394 Nursing Mothers: It is not known whether fluticasone propionate is excreted in human breast 395 milk. Subcutaneous administration of 10 mcg/kg tritiated drug to lactating rats (approximately 396 1/20 the maximum human daily inhalation dose based on mcg/m2) resulted in measurable 397 radioactivity in both plasma and milk. Because glucocorticoids are excreted in human milk, 398 caution should be exercised when fluticasone propionate inhalation aerosol is administered to a 399 nursing woman. 400 Pediatric Use: One hundred thirty-seven (137) patients between the ages of 12 and 16 years 401 were treated with FLOVENT Inhalation Aerosol in the US pivotal clinical trials. The safety and 402 effectiveness of FLOVENT Inhalation Aerosol in children below 12 years of age have not been 403 established. Oral corticosteroids have been shown to cause a reduction in growth velocity in 404 children and teenagers with extended use. If a child or teenager on any corticosteroid appears to 405 have growth suppression, the possibility that they are particularly sensitive to this effect of 406 corticosteroids should be considered (see PRECAUTIONS). 407 Geriatric Use: Five hundred seventy-four (574) patients 65 years of age or older have been 408 treated with FLOVENT Inhalation Aerosol in US and non-US clinical trials. There were no 409 differences in adverse reactions compared to those reported by younger patients. 410 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 ADVERSE REACTIONS 411 The incidence of common adverse events in Table 1 is based upon 7 placebo-controlled US 412 clinical trials in which 1,243 patients (509 female and 734 male adolescents and adults 413 previously treated with as-needed bronchodilators and/or inhaled corticosteroids) were treated 414 with FLOVENT Inhalation Aerosol (doses of 88 to 440 mcg twice daily for up to 12 weeks) or 415 placebo. 416 417 Table 1. Overall Adverse Events With >3% Incidence in US Controlled Clinical Trials 418 With FLOVENT Inhalation Aerosol in Patients Previously Receiving Bronchodilators and/or 419 Inhaled Corticosteroids 420 Adverse Event Placebo (N = 475) % FLOVENT 88 mcg Twice Daily (N = 488) % FLOVENT 220 mcg Twice Daily (N = 95) % FLOVENT 440 mcg Twice Daily (N = 185) % Ear, nose, and throat Pharyngitis 7 10 14 14 Nasal congestion 8 8 16 10 Sinusitis 4 3 6 5 Nasal discharge 3 5 4 4 Dysphonia 1 4 3 8 Allergic rhinitis 4 5 3 3 Oral candidiasis 1 2 3 5 Respiratory Upper respiratory infection 12 15 22 16 Influenza 2 3 8 5 Neurological Headache 14 17 22 17 Average duration of exposure (days) 44 66 64 59 421 Table 1 includes all events (whether considered drug-related or nondrug-related by the 422 investigator) that occurred at a rate of over 3% in groups treated with FLOVENT Inhalation 423 Aerosol and were more common than in the placebo group. In considering these data, differences 424 in average duration of exposure should be taken into account. 425 These adverse reactions were mostly mild to moderate in severity, with ≤2% of patients 426 discontinuing the studies because of adverse events. Rare cases of immediate and delayed 427 hypersensitivity reactions, including urticaria and rash and other rare events of angioedema and 428 bronchospasm, have been reported. 429 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Systemic glucocorticoid side effects were not reported during controlled clinical trials with 430 FLOVENT Inhalation Aerosol. If recommended doses are exceeded, however, or if individuals 431 are particularly sensitive, symptoms of hypercorticism, e.g., Cushing syndrome, could occur. 432 Other adverse events that occurred in these clinical trials using FLOVENT Inhalation Aerosol 433 with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were: 434 Ear, Nose, and Throat: Pain in nasal sinus(es), rhinitis. 435 Eye: Irritation of the eye(s). 436 Gastrointestinal: Nausea and vomiting, diarrhea, dyspepsia and stomach disorder. 437 Miscellaneous: Fever. 438 Mouth and Teeth: Dental problem. 439 Musculoskeletal: Pain in joint, sprain/strain, aches and pains, pain in limb. 440 Neurological: Dizziness/giddiness. 441 Respiratory: Bronchitis, chest congestion. 442 Skin: Dermatitis, rash/skin eruption. 443 Urogenital: Dysmenorrhea. 444 In a 16-week study in patients with asthma requiring oral corticosteroids, the effects of 445 FLOVENT Inhalation Aerosol, 660 mcg twice daily (N = 32) and 880 mcg twice daily (N = 32), 446 were compared with placebo. Adverse events (whether considered drug-related or 447 nondrug-related by the investigator) reported by more than 3 patients in either group treated with 448 FLOVENT Inhalation Aerosol and that were more common with FLOVENT than placebo are 449 shown below: 450 Ear, Nose, and Throat: Pharyngitis (9% and 25%), nasal congestion (19% and 22%), 451 sinusitis (19% and 22%), nasal discharge (16% and 16%), dysphonia (19% and 9%), pain in 452 nasal sinus(es) (13% and 0%), Candida-like oral lesions (16% and 9%), oropharyngeal 453 candidiasis (25% and 19%). 454 Respiratory: Upper respiratory infection (31% and 19%), influenza (0% and 13%). 455 Other: Headache (28% and 34%), pain in joint (19% and 13%), nausea and vomiting (22% 456 and 16%), muscular soreness (22% and 13%), malaise/fatigue (22% and 28%), insomnia (3% 457 and 13%). 458 Observed During Clinical Practice: In addition to adverse events reported from clinical 459 trials, the following events have been identified during postapproval use of fluticasone 460 propionate. Because they are reported voluntarily from a population of unknown size, estimates 461 of frequency cannot be made. These events have been chosen for inclusion due to either their 462 seriousness, frequency of reporting, or causal connection to fluticasone propionate or a 463 combination of these factors. 464 Ear, Nose, and Throat:\| Aphonia, facial and oropharyngeal edema, hoarseness, laryngitis, 465 and throat soreness and irritation. 466 Endocrine and Metabolic: Cushingoid features, growth velocity reduction in 467 children/adolescents, hyperglycemia, osteoporosis, and weight gain. 468 Eye: Cataracts. 469 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Non-Site Specific: Very rare anaphylactic reaction. 470 Psychiatry: Agitation, aggression, depression, and restlessness. 471 Respiratory: Asthma exacerbation, bronchospasm, chest tightness, cough, dyspnea, 472 immediate bronchospasm, paradoxical bronchospasm, pneumonia, and wheeze. 473 Skin: Contusions, cutaneous hypersensitivity reactions, ecchymoses, and pruritus. 474 Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may 475 present with systemic eosinophilic conditions, with some patients presenting with clinical 476 features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated 477 with systemic corticosteroid therapy. These events usually, but not always, have been associated 478 with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of 479 fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with 480 other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, 481 vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy 482 presenting in their patients. A causal relationship between fluticasone propionate and these 483 underlying conditions has not been established (see PRECAUTIONS: Eosinophilic Conditions). 484 OVERDOSAGE 485 Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS). 486 Inhalation by healthy volunteers of a single dose of 1,760 or 3,520 mcg of fluticasone propionate 487 inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at doses 488 of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. 489 Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 490 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or 491 moderate severity, and incidences were similar in active and placebo treatment groups. The oral 492 and subcutaneous median lethal doses in rats and mice were >1,000 mg/kg (>2,000 times the 493 maximum human daily inhalation dose based on mg/m2). 494 DOSAGE AND ADMINISTRATION 495 FLOVENT Inhalation Aerosol should be administered by the orally inhaled route in patients 496 12 years of age and older. Individual patients will experience a variable time to onset and degree 497 of symptom relief. Generally, FLOVENT Inhalation Aerosol has a relatively rapid onset of 498 action for an inhaled glucocorticoid. Improvement in asthma control following inhaled 499 administration of fluticasone propionate can occur within 24 hours of beginning treatment, 500 although maximum benefit may not be achieved for 1 to 2 weeks or longer after starting 501 treatment. 502 After asthma stability has been achieved (see Table 2), it is always desirable to titrate to the 503 lowest effective dosage to reduce the possibility of side effects. For patients who do not respond 504 adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide 505 additional asthma control. The safety and efficacy of FLOVENT Inhalation Aerosol when 506 administered in excess of recommended dosages have not been established. 507 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 The recommended starting dosage and the highest recommended dosage of FLOVENT 508 Inhalation Aerosol, based on prior antiasthma therapy, are listed in Table 2. 509 510 Table 2. Recommended Dosages of FLOVENT Inhalation Aerosol 511 Previous Therapy Recommended Starting Dosage Highest Recommended Dosage Bronchodilators alone 88 mcg twice daily 440 mcg twice daily Inhaled corticosteroids 88-220 mcg twice daily* 440 mcg twice daily Oral corticosteroids† 880 mcg twice daily 880 mcg twice daily * Starting dosages above 88 mcg twice daily may be considered for patients with poorer asthma 512 control or those who have previously required doses of inhaled corticosteroids that are in the 513 higher range for that specific agent. 514 NOTE: In all patients, it is desirable to titrate to the lowest effective dosage once asthma 515 stability is achieved. 516 † For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone 517 should be reduced no faster than 2.5 mg/day on a weekly basis, beginning after at least 518 1 week of therapy with FLOVENT Inhalation Aerosol. Patients should be carefully monitored 519 for signs of asthma instability, including serial objective measures of airflow, and for signs of 520 adrenal insufficiency (see WARNINGS). Once prednisone reduction is complete, the dosage 521 of fluticasone propionate should be reduced to the lowest effective dosage. 522 523 Geriatric Use: In studies where geriatric patients (65 years of age or older, see 524 PRECAUTIONS) have been treated with FLOVENT Inhalation Aerosol, efficacy and safety did 525 not differ from that in younger patients. Consequently, no dosage adjustment is recommended. 526 Directions for Use: Illustrated Patient’s Instructions for Use accompany each package of 527 FLOVENT Inhalation Aerosol. 528 HOW SUPPLIED 529 FLOVENT 44 mcg Inhalation Aerosol is supplied in 7.9-g canisters containing 60 metered 530 inhalations in institutional pack boxes of 1 (NDC 0173-0497-00) and in 13-g canisters containing 531 120 metered inhalations in boxes of 1 (NDC 0173-0491-00). Each canister is supplied with a 532 dark orange oral actuator with a peach strapcap and patient’s instructions. Each actuation of the 533 inhaler delivers 44 mcg of fluticasone propionate from the actuator. 534 FLOVENT 110 mcg Inhalation Aerosol is supplied in 7.9-g canisters containing 60 metered 535 inhalations in institutional pack boxes of 1 (NDC 0173-0498-00) and in 13-g canisters containing 536 120 metered inhalations in boxes of 1 (NDC 0173-0494-00). Each canister is supplied with a 537 dark orange oral actuator with a peach strapcap and patient’s instructions. Each actuation of the 538 inhaler delivers 110 mcg of fluticasone propionate from the actuator. 539 FLOVENT 220 mcg Inhalation Aerosol is supplied in 7.9-g canisters containing 60 metered 540 inhalations in institutional pack boxes of 1 (NDC 0173-0499-00) and in 13-g canisters containing 541 120 metered inhalations in boxes of 1 (NDC 0173-0495-00). Each canister is supplied with a 542 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 dark orange oral actuator with a peach strapcap and patient’s instructions. Each actuation of the 543 inhaler delivers 220 mcg of fluticasone propionate from the actuator. 544 FLOVENT canisters are for use with FLOVENT Inhalation Aerosol actuators only. The 545 actuators should not be used with other aerosol medications. 546 The correct amount of medication in each inhalation cannot be assured after 60 inhalations 547 from the 7.9-g canister or 120 inhalations from the 13-g canister even though the canister is not 548 completely empty. The canister should be discarded when the labeled number of actuations has 549 been used. 550 Store between 2° and 30°C (36° and 86°F). Store canister with mouthpiece down. Protect 551 from freezing temperatures and direct sunlight. 552 Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store 553 at temperatures above 120°F. Keep out of reach of children. For best results, the canister should 554 be at room temperature before use. Shake well before using. 555 556 Note: The indented statement below is required by the Federal Government’s Clean Air Act for 557 all products containing or manufactured with chlorofluorocarbons (CFCs). 558 559 WARNING: Contains trichlorofluoromethane and dichlorodifluoromethane, substances that 560 harm public health and environment by destroying ozone in the upper atmosphere. 561 562 A notice similar to the above WARNING has been placed in the patient information leaflet of 563 this product pursuant to EPA regulations. 564 565 566 567 GlaxoSmithKline 568 Research Triangle Park, NC 27709 569 570 ©Year, GlaxoSmithKline. All rights reserved. 571 572 Month Year RL- 573 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patient’s Instructions for Use FLOVENT® 44 mcg (fluticasone propionate, 44 mcg) Inhalation Aerosol FLOVENT® 110 mcg (fluticasone propionate, 110 mcg) Inhalation Aerosol FLOVENT® 220 mcg (fluticasone propionate, 220 mcg) Inhalation Aerosol Please read this leaflet carefully before you start to take your medicine. It provides a summary of information on your medicine. For further information ask your doctor or pharmacist. WHAT YOU SHOULD KNOW ABOUT FLOVENT® INHALATION AEROSOL Your doctor has prescribed FLOVENT 44 mcg Inhala- tion Aerosol, FLOVENT 110 mcg Inhalation Aerosol, or FLOVENT 220 mcg Inhalation Aerosol. It contains a medicine called fluticasone propionate, which is a synthetic glucocorticoid. Glucocorticoids are natural substances found in the body that help fight inflammation. They are used to treat asthma because they reduce the swelling and irritation in the walls of the small air passages in the lungs and ease breathing problems. When inhaled regu- larly, glucocorticoids also help to prevent attacks of asthma. IMPORTANT POINTS TO REMEMBER ABOUT FLOVENT INHALATION AEROSOL 1 MAKE SURE that this medicine is suitable for you (see “BEFORE USING YOUR INHALER” below). 2 It is important that you inhale each dose as your doctor has advised. If you are not sure, ask your doctor or pharmacist. 3 Use your inhaler as directed by your doctor. DO NOT STOP THE TREATMENT EVEN IF YOU FEEL BETTER unless told to do so by your doctor. 4 DO NOT inhale more doses or use this inhaler more often than instructed by your doctor. 5 This medicine is NOT intended to provide rapid relief of your breathing difficulties during an asthma attack. It must be taken at regular inter- vals as recommended by your doctor, and not as an emergency measure. 6 Your doctor may prescribe additional medicine (such as bronchodilators) for emergency relief if an acute asthma attack occurs. Please contact your doctor if: • an asthma attack does not respond to the additional medicine • you require more of the additional medicine than usual. 7 If you also use another medicine by inhalation, you should consult your doctor for instructions on when to use it in relation to using FLOVENT Inhalation Aerosol. BEFORE USING YOUR INHALER TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDICINE: N if you are pregnant (or intending to become pregnant), N if you are breastfeeding a baby, N if you are allergic to FLOVENT Inhalation Aerosol, or any other orally inhaled glucocorticoid, N if you are taking a medicine containing ritonavir (commonly used to treat HIV infection or AIDS). In some circumstances, this medicine may not be suitable and your doctor may wish to give you a different medicine. Make sure that your doctor knows what other medicines you are taking. USING YOUR INHALER N Follow the instructions shown on the next few pages. If you have any problems, tell your doctor or pharmacist. N It is important that you inhale each dose as directed by your doctor. The label will usually tell you what dose to take and how often. If it doesn’t, or you are not sure, ask your doctor or pharmacist. DOSAGE N Use as directed by your doctor. N It is VERY IMPORTANT that you follow your doctor’s instructions as to how many inhala- tions to inhale and how often to use your inhaler. N DO NOT inhale more doses or use your inhaler more often than your doctor advises. N It may take 1 to 2 weeks or longer for this medicine to work and it is VERY IMPORTANT THAT YOU USE IT REGULARLY. DO NOT STOP TREATMENT EVEN IF YOU ARE FEELING BETTER unless told to do so by your doctor. N If you miss a dose, just take your regularly scheduled next dose when it is due. DO NOT DOUBLE the dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW TO USE YOUR INHALER Read the complete instructions carefully and use only as directed. 1 SHAKE THE INHALER WELL for 15 seconds immediately before each use (see Figure 1). 2 REMOVE THE CAP FROM THE MOUTHPIECE (see Figure 2); the strap on the cap will stay attached to the actuator. If the strap is removed from the actuator and lost, the inhaler mouthpiece should be inspected for the presence of foreign objects before each use. Make sure the canister is fully and firmly inserted into the actuator. As with all aerosol medicine, it is recom- mended to “test spray” the inhaler. Do this by spraying 4 times into the air before using for the first time and when the inhaler has not been used for 4 weeks or longer. You should also spray once into the air before using when the inhaler has not been used for 1 to 3 weeks. Avoid spraying in eyes. 3 BREATHE OUT THROUGH THE MOUTH (see Figure 3a). Place the mouthpiece in the mouth, holding the inhaler in the posi- tion shown in Figure 3a and closing the lips around it. Alternatively, the inhaler may be positioned 1 to 2 inches away from the open mouth (see Figure 3b). 4 WHILE BREATHING IN DEEPLY AND SLOWLY THROUGH THE MOUTH, PRESS DOWN FIRMLY AND FULLY ON THE TOP OF THE METAL CAN- ISTER with your index finger (see Figure 4). 5 CONTINUE TO INHALE AND TRY TO HOLD YOUR BREATH FOR 10 SECONDS. Before breathing out, remove the inhaler from your mouth and release your finger from the canister. 6 WAIT ABOUT 30 SECONDS AND SHAKE the inhaler again. Repeat steps 3 through 5 for each inhalation prescribed by your doctor. 7 REPLACE THE MOUTHPIECE CAP AFTER EACH USE. 8 RINSE YOUR MOUTH with water after you finish taking a dose. Do not swallow. 9 CLEANSE THE INHALER THOROUGHLY AND FREQUENTLY. Remove the metal canister and cleanse the plastic case and cap by rinsing thor- oughly in warm, running water at least once a day. After thoroughly drying the plastic case and cap, gently replace the canister into the case with a twisting motion and replace the cap. 10 DISCARD THE CANISTER AFTER YOU HAVE USED THE LABELED NUMBER OF INHALATIONS. The correct amount of medicine in each inhalation cannot be assured after this point. You should keep track of the number of actuations used from each canister of FLOVENT Inhalation Aerosol, and discard the canister after 120 actuations from the 13-g can- ister or 60 actuations from the 7.9-g canister. STORING YOUR INHALER N Keep your inhaler out of the reach of children. N Store between 2° and 30°C (36° and 86°F). Store canister with mouthpiece down. Protect from freezing temperatures and direct sunlight. N For best results, the canister should be at room temperature before use. N FLOVENT canisters are for use with FLOVENT Inha- lation Aerosol actuators only. The actuator should not be used with other aerosol medicines. N DO NOT use after the date shown as “EXP” on the label or box. REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT give this medi- cine to anyone else. FURTHER INFORMATION This leaflet does not contain the complete infor- mation about your medicine. If you have any questions, or are not sure about something, then you should ask your doctor or pharmacist. You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine. Note: The indented statement below is required by the Federal Government’s Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs). This product contains trichlorofluoromethane and dichlorodifluoromethane, substances which harm the environment by depleting ozone in the upper atmosphere. Your doctor has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR DOCTOR. If you have any questions about alternatives, consult with your doctor. Figure 1 Figure 2 Figure 3a Figure 3b Figure 4 GlaxoSmithKline Research Triangle Park, NC 27709 ©2003, GlaxoSmithKline. All rights reserved. July 2003 RL-2022 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 PRESCRIBING INFORMATION 1 FLOVENT® ROTADISK® 50 mcg 2 (fluticasone propionate inhalation powder, 50 mcg) 3 4 FLOVENT® ROTADISK® 100 mcg 5 (fluticasone propionate inhalation powder, 100 mcg) 6 7 FLOVENT® ROTADISK® 250 mcg 8 (fluticasone propionate inhalation powder, 250 mcg) 9 10 For Oral Inhalation Only 11 For Use With the DISKHALER® Inhalation Device 12 DESCRIPTION 13 The active component of FLOVENT ROTADISK 50 mcg, FLOVENT ROTADISK 100 mcg, 14 and FLOVENT ROTADISK 250 mcg is fluticasone propionate, a corticosteroid having the 15 chemical name S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta- 16 1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: 17 18 19 20 Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6, and 21 the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in 22 dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. 23 FLOVENT ROTADISK 50 mcg, FLOVENT ROTADISK 100 mcg, and FLOVENT 24 ROTADISK 250 mcg contain a dry powder presentation of fluticasone propionate intended for 25 oral inhalation only. Each double-foil ROTADISK contains 4 blisters. Each blister contains a 26 mixture of 50, 100, or 250 mcg of microfine fluticasone propionate blended with lactose (which 27 contains milk proteins) to a total weight of 25 mg. The contents of each blister are inhaled using 28 a specially designed plastic device for inhaling powder called the DISKHALER. After a 29 fluticasone propionate ROTADISK is loaded into the DISKHALER, a blister containing 30 medication is pierced and the fluticasone propionate is dispersed into the air stream created 31 when the patient inhales through the mouthpiece. 32 The amount of drug delivered to the lung will depend on patient factors such as inspiratory 33 flow. Under standardized in vitro testing, FLOVENT ROTADISK delivers 44, 88, or 220 mcg 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 of fluticasone propionate from FLOVENT ROTADISK 50 mcg, FLOVENT ROTADISK 35 100 mcg, or FLOVENT ROTADISK 250 mcg, respectively, when tested at a flow rate of 36 60 L/min for 3 seconds. In adult and adolescent patients with asthma, mean peak inspiratory 37 flow (PIF) through the DISKHALER was 123 L/min (range, 88 to 159 L/min), and in pediatric 38 patients 4 to 11 years of age with asthma, mean PIF was 110 L/min (range, 43 to 175 L/min). 39 CLINICAL PHARMACOLOGY 40 Fluticasone propionate is a synthetic, trifluorinated corticosteroid with potent 41 anti-inflammatory activity. In vitro assays using human lung cytosol preparations have 42 established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 43 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate 44 (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of 45 budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these 46 results. 47 The precise mechanisms of fluticasone propionate action in asthma are unknown. 48 Inflammation is recognized as an important component in the pathogenesis of asthma. 49 Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, 50 basophils, lymphocytes, macrophages, and neutrophils) and mediator production or secretion 51 (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. 52 These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. 53 Though highly effective for the treatment of asthma, corticosteroids do not affect asthma 54 symptoms immediately. However, improvement following inhaled administration of fluticasone 55 propionate can occur within 24 hours of beginning treatment, although maximum benefit may 56 not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are 57 discontinued, asthma stability may persist for several days or longer. 58 Pharmacokinetics: Absorption: The activity of FLOVENT ROTADISK Inhalation Powder 59 is due to the parent drug, fluticasone propionate. Studies using oral dosing of labeled and 60 unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate 61 is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the 62 gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is 63 systemically absorbed. The systemic bioavailability of fluticasone propionate inhalation powder 64 in healthy volunteers averaged about 13.5% of the nominal dose. 65 Peak plasma concentrations after a 1,000-mcg dose of fluticasone propionate inhalation 66 powder ranged from 0.1 to 1.0 ng/mL. 67 Distribution: Following intravenous administration, the initial disposition phase for 68 fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. 69 The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound 70 to human plasma proteins averaged 91%. 71 Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone 72 propionate is not significantly bound to human transcortin. 73 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), 74 with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite 75 detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed 76 through the cytochrome P450 3A4 pathway. This metabolite had approximately 2,000 times less 77 affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and 78 negligible pharmacological activity in animal studies. Other metabolites detected in vitro using 79 cultured human hepatoma cells have not been detected in man. 80 In a multiple-dose drug interaction study, coadministration of fluticasone propionate 81 (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone 82 propionate pharmacokinetics. 83 In a drug interaction study, coadministration of fluticasone propionate (1,000 mcg) and 84 ketoconazole (200 mg once daily) resulted in increased fluticasone propionate concentrations, a 85 reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. 86 Excretion: Following intravenous dosing, fluticasone propionate showed polyexponential 87 kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a 88 radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in 89 the feces as parent drug and metabolites. 90 Special Populations: Formal pharmacokinetic studies using fluticasone propionate were 91 not carried out in any special populations. In a clinical study using fluticasone propionate 92 inhalation powder, trough fluticasone propionate plasma concentrations were collected in 76 93 males and 74 females after inhaled administration of 100 and 500 mcg twice daily. Full 94 pharmacokinetic profiles were obtained from 7 female patients and 13 male patients at these 95 doses, and no overall differences in pharmacokinetic behavior were found. 96 Plasma concentrations of fluticasone propionate were measured 20 and 40 minutes after 97 dosing from 29 children aged 4 to 11 years who were taking either 50 or 100 mcg twice daily of 98 fluticasone propionate inhalation powder. Plasma concentration values ranged from below the 99 limit of quantitation (25 pg/mL) to 117 pg/mL (50-mcg dose) or 154 pg/mL (100-mcg dose). In a 100 study with adults taking the 100-mcg twice-daily dose, the plasma concentrations observed 101 ranged from below the limit of quantitation to 73.1 pg/mL. The median fluticasone propionate 102 plasma concentrations for the 100-mcg dose in children was 58.7 pg/mL; in adults the median 103 plasma concentration was 39.5 pg/mL. 104 Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. 105 Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor 106 ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 107 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was 108 coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate 109 concentrations following fluticasone propionate aqueous nasal spray alone were undetectable 110 (<10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax 111 averaged 11.9 pg/mL [range, 10.8 to 14.1 pg/mL] and AUC(0-τ) averaged 8.43 pg•hr/mL [range, 112 4.2 to 18.8 pg•hr/mL]). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range, 113 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, 114 after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This 115 significant increase in plasma fluticasone propionate exposure resulted in a significant decrease 116 (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC). 117 Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are 118 coadministered with fluticasone propionate. In a drug interaction study, coadministration of 119 orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted 120 in increased plasma fluticasone propionate exposure and reduced plasma cortisol AUC, but had 121 no effect on urinary excretion of cortisol. 122 In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone 123 propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect 124 fluticasone propionate pharmacokinetics. 125 Pharmacodynamics: To confirm that systemic absorption does not play a role in the clinical 126 response to inhaled fluticasone propionate, a double-blind clinical study comparing inhaled and 127 oral fluticasone propionate was conducted. Doses of 100 and 500 mcg twice daily of fluticasone 128 propionate inhalation powder were compared to oral fluticasone propionate, 20,000 mcg given 129 once daily, and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in 130 all 3 active groups, but the mean values were highest in the oral group. Both doses of inhaled 131 fluticasone propionate were effective in maintaining asthma stability and improving lung 132 function while oral fluticasone propionate and placebo were ineffective. This demonstrates that 133 the clinical effectiveness of inhaled fluticasone propionate is due to its direct local effect and not 134 to an indirect effect through systemic absorption. 135 The potential systemic effects of inhaled fluticasone propionate on the 136 hypothalamic-pituitary-adrenal (HPA) axis were also studied in patients with asthma. 137 Fluticasone propionate given by inhalation aerosol at doses of 220, 440, 660, or 880 mcg twice 138 daily was compared with placebo or oral prednisone 10 mg given once daily for 4 weeks. For 139 most patients, the ability to increase cortisol production in response to stress, as assessed by 140 6-hour cosyntropin stimulation, remained intact with inhaled fluticasone propionate treatment. 141 No patient had an abnormal response (peak serum cortisol <18 mcg/dL) after dosing with 142 placebo or fluticasone propionate 220 mcg twice daily. For patients treated with 440, 660, and 143 880 mcg twice daily, 10%, 16%, and 12%, respectively, had an abnormal response as compared 144 to 29% of patients treated with prednisone. 145 In clinical trials with fluticasone propionate inhalation powder, using doses up to and 146 including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol 147 <18 mcg/dL) were noted in patients receiving fluticasone propionate or placebo. The incidence 148 of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year study carried out 149 in 64 patients randomized to fluticasone propionate 500 mcg twice daily or placebo, 1 patient 150 receiving fluticasone propionate (4%) had an abnormal response to 6-hour cosyntropin infusion 151 at 1 year; repeat testing at 18 months and 2 years was normal. Another patient receiving 152 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 fluticasone propionate (5%) had an abnormal response at 2 years. No patient on placebo had an 153 abnormal response at 1 or 2 years. 154 CLINICAL TRIALS 155 Double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,197 156 adolescent and adult patients with asthma to assess the efficacy and safety of FLOVENT 157 ROTADISK in the treatment of asthma. Fixed doses of 50, 100, 250, and 500 mcg twice daily 158 were compared to placebo to provide information about appropriate dosing to cover a range of 159 asthma severity. Patients with asthma included in these studies were those not adequately 160 controlled with beta-agonists alone, and those already maintained on daily inhaled 161 corticosteroids. In these efficacy trials, at all doses, measures of pulmonary function (forced 162 expiratory volume in 1 second [FEV1] and morning peak expiratory flow [AM PEF]) were 163 statistically significantly improved as compared with placebo. All doses were delivered by 164 inhalation of the contents of 1 or 2 blisters from the DISKHALER twice daily. 165 Figure 1 displays results of pulmonary function tests for 2 recommended dosages of 166 FLOVENT ROTADISK (100 and 250 mcg twice daily) and placebo from a 12-week trial in 331 167 adolescent and adult patients with asthma (baseline FEV1 = 2.63 L/sec) inadequately controlled 168 on bronchodilators alone. Because this trial used predetermined criteria for lack of efficacy, 169 which caused more patients in the placebo group to be withdrawn, pulmonary function results at 170 Endpoint, which is the last evaluable FEV1 result and includes most patients’ lung function data, 171 are also provided. Pulmonary function at both dosages of FLOVENT ROTADISK improved 172 significantly compared with placebo by the first week of treatment, and this improvement was 173 maintained over the duration of the trial. 174 175 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Figure 1. A 12-Week Clinical Trial in Patients Inadequately Controlled 176 on Bronchodilators Alone: Mean Percent Change From Baseline 177 in FEV1 Prior to AM Dose 178 179 180 181 In a second clinical study of 75 patients, 500 mcg twice daily was evaluated in a similar 182 population. In this trial FLOVENT ROTADISK significantly improved pulmonary function as 183 compared with placebo. 184 Figure 2 displays results of pulmonary function tests for 2 recommended dosages of 185 FLOVENT ROTADISK (100 and 250 mcg twice daily) and placebo from a 12-week trial in 342 186 adolescent and adult patients with asthma (baseline FEV1 = 2.49 L/sec) already receiving daily 187 inhaled corticosteroid therapy (≥336 mcg/day of beclomethasone dipropionate or ≥800 mcg/day 188 of triamcinolone acetonide) in addition to as-needed albuterol and theophylline (38% of all 189 patients). Because this trial also used predetermined criteria for lack of efficacy, which caused 190 more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint are 191 included. Pulmonary function at both dosages of FLOVENT ROTADISK improved significantly 192 compared with placebo by the first week of treatment, and the improvement was maintained over 193 the duration of the trial. 194 195 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Figure 2. A 12-Week Clinical Trial in Patients Already Receiving Inhaled 196 Corticosteroids: Mean Percent Change From Baseline in FEV1 Prior to 197 AM Dose 198 199 200 201 In a second clinical study of 139 patients, treatment with 500 mcg twice daily was evaluated 202 in a similar patient population. In this trial FLOVENT ROTADISK significantly improved 203 pulmonary function as compared with placebo. 204 In the 4 trials described above, all dosages of FLOVENT ROTADISK were efficacious; 205 however, at higher dosages, patients were less likely to discontinue study participation due to 206 asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung 207 function and patient-recorded variables such as AM PEF, albuterol use, and nighttime 208 awakenings due to asthma). 209 In a clinical trial of 96 patients with severe asthma requiring chronic oral prednisone therapy 210 (average baseline daily prednisone dose was 10 mg), fluticasone propionate given by inhalation 211 aerosol at doses of 660 and 880 mcg twice daily was evaluated. Both doses enabled a 212 statistically significantly larger percentage of patients to wean successfully from oral prednisone 213 as compared with placebo (69% of the patients on 660 mcg twice daily and 88% of the patients 214 on 880 mcg twice daily as compared with 3% of patients on placebo). Accompanying the 215 reduction in oral corticosteroid use, patients treated with fluticasone propionate had significantly 216 improved lung function and fewer asthma symptoms as compared with the placebo group. These 217 data were obtained from a clinical study using fluticasone propionate inhalation aerosol; no 218 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 direct assessment of the clinical comparability of equal nominal doses for the FLOVENT 219 ROTADISK and FLOVENT Inhalation Aerosol formulations in this population has been 220 conducted. 221 Pediatric Experience: In a 12-week, placebo-controlled clinical trial of 263 patients aged 222 4 to 11 years inadequately controlled on bronchodilators alone (baseline morning peak 223 expiratory flow = 200 L/min), fluticasone propionate inhalation powder doses of 50 and 224 100 mcg twice daily significantly improved morning peak expiratory flow (28% and 34% 225 change from baseline at Endpoint, respectively) compared to placebo (11% change). In a second 226 placebo-controlled, 52-week trial of 325 patients aged 4 to 11 years, approximately half of 227 whom were receiving inhaled corticosteroids at baseline, doses of fluticasone propionate 228 inhalation powder of 50 and 100 mcg twice daily improved lung function by the first week of 229 treatment, and the improvement continued over 1 year compared to placebo. In both studies, 230 patients on active treatment were significantly less likely to discontinue treatment due to lack of 231 efficacy. 232 INDICATIONS AND USAGE 233 FLOVENT ROTADISK is indicated for the maintenance treatment of asthma as prophylactic 234 therapy in patients 4 years of age and older. It is also indicated for patients requiring oral 235 corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate 236 their requirement for oral corticosteroids over time. 237 FLOVENT ROTADISK is NOT indicated for the relief of acute bronchospasm. 238 CONTRAINDICATIONS 239 FLOVENT ROTADISK is contraindicated in the primary treatment of status asthmaticus or 240 other acute episodes of asthma where intensive measures are required. 241 Hypersensitivity to any of the ingredients of these preparations contraindicates their use (see 242 DESCRIPTION and ADVERSE REACTIONS: Observed During Clinical Practice: Non-Site 243 Specific). 244 WARNINGS 245 Particular care is needed for patients who are transferred from systemically active 246 corticosteroids to FLOVENT ROTADISK because deaths due to adrenal insufficiency have 247 occurred in patients with asthma during and after transfer from systemic corticosteroids to less 248 systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a 249 number of months are required for recovery of HPA function. 250 Patients who have been previously maintained on 20 mg or more per day of prednisone (or its 251 equivalent) may be most susceptible, particularly when their systemic corticosteroids have been 252 almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs 253 and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection 254 (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although 255 FLOVENT ROTADISK may provide control of asthma symptoms during these episodes, in 256 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 recommended doses it supplies less than normal physiological amounts of corticosteroid 257 systemically and does NOT provide the mineralocorticoid activity that is necessary for coping 258 with these emergencies. 259 During periods of stress or a severe asthma attack, patients who have been withdrawn from 260 systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) 261 immediately and to contact their physicians for further instruction. These patients should also be 262 instructed to carry a warning card indicating that they may need supplementary systemic 263 corticosteroids during periods of stress or a severe asthma attack. 264 A drug interaction study in healthy subjects has shown that ritonavir (a highly potent 265 cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate 266 exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL 267 PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions). During 268 postmarketing use, there have been reports of clinically significant drug interactions in patients 269 receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects 270 including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone 271 propionate and ritonavir is not recommended unless the potential benefit to the patient 272 outweighs the risk of systemic corticosteroid side effects. 273 Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid 274 use after transferring to FLOVENT ROTADISK. In a clinical trial of 96 patients, prednisone 275 reduction was successfully accomplished by reducing the daily prednisone dose by 2.5 mg on a 276 weekly basis during transfer to inhaled fluticasone propionate. Successive reduction of 277 prednisone dose was allowed only when lung function, symptoms, and as-needed beta-agonist 278 use were better than or comparable to that seen before initiation of prednisone dose reduction. 279 Lung function (FEV1 or AM PEF), beta-agonist use, and asthma symptoms should be carefully 280 monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and 281 symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as 282 fatigue, lassitude, weakness, nausea and vomiting, and hypotension. 283 Transfer of patients from systemic corticosteroid therapy to FLOVENT ROTADISK may 284 unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, 285 conjunctivitis, eczema, arthritis. 286 Persons who are on drugs that suppress the immune system are more susceptible to infections 287 than healthy individuals. Chickenpox and measles, for example, can have a more serious or even 288 fatal course in susceptible children or adults on corticosteroids. In such children or adults who 289 have not had these diseases, particular care should be taken to avoid exposure. How the dose, 290 route, and duration of corticosteroid administration affect the risk of developing a disseminated 291 infection is not known. The contribution of the underlying disease and/or prior corticosteroid 292 treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella 293 zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with 294 pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package 295 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment 296 with antiviral agents may be considered. 297 FLOVENT ROTADISK is not to be regarded as a bronchodilator and is not indicated for 298 rapid relief of bronchospasm. 299 As with other inhaled asthma medications, bronchospasm may occur with an immediate 300 increase in wheezing after dosing. If bronchospasm occurs following dosing with FLOVENT 301 ROTADISK, it should be treated immediately with a fast-acting inhaled bronchodilator. 302 Treatment with FLOVENT ROTADISK should be discontinued and alternative therapy 303 instituted. 304 Patients should be instructed to contact their physicians immediately when episodes of 305 asthma that are not responsive to bronchodilators occur during the course of treatment with 306 FLOVENT ROTADISK. During such episodes, patients may require therapy with oral 307 corticosteroids. 308 PRECAUTIONS 309 General: During withdrawal from oral corticosteroids, some patients may experience 310 symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, 311 lassitude, and depression, despite maintenance or even improvement of respiratory function. 312 Fluticasone propionate will often permit control of asthma symptoms with less suppression of 313 HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone 314 propionate is absorbed into the circulation and can be systemically active at higher doses, the 315 beneficial effects of FLOVENT ROTADISK in minimizing HPA dysfunction may be expected 316 only when recommended dosages are not exceeded and individual patients are titrated to the 317 lowest effective dose. A relationship between plasma levels of fluticasone propionate and 318 inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment 319 with FLOVENT Inhalation Aerosol. Since individual sensitivity to effects on cortisol production 320 exists, physicians should consider this information when prescribing FLOVENT ROTADISK. 321 Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated 322 with these drugs should be observed carefully for any evidence of systemic corticosteroid 323 effects. Particular care should be taken in observing patients postoperatively or during periods of 324 stress for evidence of inadequate adrenal response. 325 It is possible that systemic corticosteroid effects such as hypercorticism and adrenal 326 suppression (including adrenal crisis) may appear in a small number of patients, particularly 327 when FLOVENT ROTADISK is administered at higher than recommended doses over 328 prolonged periods of time. If such effects occur, FLOVENT ROTADISK should be reduced 329 slowly, consistent with accepted procedures for reducing systemic corticosteroids and for 330 management of asthma symptoms. 331 A reduction of growth velocity in children or adolescents may occur as a result of poorly 332 controlled asthma or from the therapeutic use of corticosteroids, including inhaled 333 corticosteroids. A 52-week placebo-controlled study to assess the potential growth effects of 334 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 FLOVENT ROTADISK at 50 and 100 mcg twice daily was conducted in the US in 325 335 prepubescent children (244 males and 81 females) 4 to 11 years of age. The mean growth 336 velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo 337 group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg 338 group (n = 89). An imbalance in the proportion of children entering puberty between groups and 339 a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding 340 factors in interpreting these data. A separate subset analysis of children who remained 341 prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo 342 group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg 343 group (n = 79). The clinical significance of these growth data is not certain. In children 8.5 years 344 of age, the mean age of children in this study, the range for expected growth velocity is: boys – 345 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; 346 girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th 347 percentile = 7.3 cm/year. The effects of long-term treatment of children with inhaled 348 corticosteroids, including fluticasone propionate, on final adult height are not known. Physicians 349 should closely follow the growth of children and adolescents taking corticosteroids by any route, 350 and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if 351 growth appears slowed. Patients should be maintained on the lowest dose of inhaled 352 corticosteroid that effectively controls their asthma. 353 The long-term effects of fluticasone propionate in human subjects are not fully known. In 354 particular, the effects resulting from chronic use of fluticasone propionate on developmental or 355 immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Some patients 356 have received inhaled fluticasone propionate on a continuous basis for periods of 3 years or 357 longer. In clinical studies with patients treated for 2 years with inhaled fluticasone propionate, 358 no apparent differences in the type or severity of adverse reactions were observed after long- 359 versus short-term treatment. 360 Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported 361 following the inhaled administration of corticosteroids, including fluticasone propionate. 362 In clinical studies with inhaled fluticasone propionate, the development of localized 363 infections of the pharynx with Candida albicans has occurred. When such an infection develops, 364 it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while 365 remaining on treatment with FLOVENT ROTADISK, but at times therapy with FLOVENT 366 ROTADISK may need to be interrupted. 367 Inhaled corticosteroids should be used with caution, if at all, in patients with active or 368 quiescent tuberculous infections of the respiratory tract; untreated systemic fungal, bacterial, 369 viral, or parasitic infections; or ocular herpes simplex. 370 Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may 371 present with systemic eosinophilic conditions, with some patients presenting with clinical 372 features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated 373 with systemic corticosteroid therapy. These events usually, but not always, have been associated 374 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of 375 fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with 376 other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, 377 vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy 378 presenting in their patients. A causal relationship between fluticasone propionate and these 379 underlying conditions has not been established (see ADVERSE REACTIONS). 380 Information for Patients: Patients being treated with FLOVENT ROTADISK should receive 381 the following information and instructions. This information is intended to aid them in the safe 382 and effective use of this medication. It is not a disclosure of all possible adverse or intended 383 effects. 384 Patients should use FLOVENT ROTADISK at regular intervals as directed. Results of 385 clinical trials indicated significant improvement may occur within the first day or two of 386 treatment; however, the full benefit may not be achieved until treatment has been administered 387 for 1 to 2 weeks or longer. The patient should not increase the prescribed dosage but should 388 contact the physician if symptoms do not improve or if the condition worsens. 389 Patients should be warned to avoid exposure to chickenpox or measles and, if they are 390 exposed, to consult their physicians without delay. 391 For the proper use of FLOVENT ROTADISK and to attain maximum improvement, the 392 patient should read and follow carefully the Patient’s Instructions for Use accompanying the 393 product. 394 Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug 395 interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown 396 that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma 397 fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations 398 (see CLINICAL PHARMACOLOGY: Drug Interactions). During postmarketing use, there have 399 been reports of clinically significant drug interactions in patients receiving fluticasone propionate 400 and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and 401 adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not 402 recommended unless the potential benefit to the patient outweighs the risk of systemic 403 corticosteroid side effects. 404 In a placebo-controlled, crossover study in 8 healthy volunteers, coadministration of a single 405 dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole 406 (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a 407 reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should 408 be exercised when FLOVENT ROTADISK is coadministered with ketoconazole and other 409 known potent cytochrome P450 3A4 inhibitors. 410 Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluticasone propionate 411 demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 412 2 times the maximum recommended daily inhalation dose in adults and approximately 10 times 413 the maximum recommended daily inhalation dose in children on a mcg/m2 basis) for 78 weeks 414 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 or in rats at inhalation doses up to 57 mcg/kg (approximately 1/4 the maximum recommended 415 daily inhalation dose in adults and comparable to the maximum recommended daily inhalation 416 dose in children on a mcg/m2 basis) for 104 weeks. 417 Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in 418 vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in 419 vitro or in the mouse micronucleus test when administered at high doses by the oral or 420 subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone 421 marrow. 422 No evidence of impairment of fertility was observed in reproductive studies conducted in 423 male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 1/5 the maximum 424 recommended daily inhalation dose in adults on a mcg/m2 basis). Prostate weight was 425 significantly reduced at a subcutaneous dose of 50 mcg/kg. 426 Pregnancy: Teratogenic Effects: Pregnancy Category C. Subcutaneous studies in the 427 mouse and rat at 45 and 100 mcg/kg, respectively (approximately 1/10 and 1/3, respectively, the 428 maximum recommended daily inhalation dose in adults on a mcg/m2 basis), revealed fetal 429 toxicity characteristic of potent corticosteroid compounds, including embryonic growth 430 retardation, omphalocele, cleft palate, and retarded cranial ossification. 431 In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 432 4 mcg/kg (approximately 1/30 the maximum recommended daily inhalation dose in adults on a 433 mcg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg 434 (approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/m2 435 basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this 436 study, consistent with the established low bioavailability following oral administration (see 437 CLINICAL PHARMACOLOGY). 438 Fluticasone propionate crossed the placenta following oral administration of 100 mcg/kg to 439 rats or 300 mcg/kg to rabbits (approximately 1/3 and 2 times, respectively, the maximum 440 recommended daily inhalation dose in adults on a mcg/m2 basis). 441 There are no adequate and well-controlled studies in pregnant women. FLOVENT 442 ROTADISK should be used during pregnancy only if the potential benefit justifies the potential 443 risk to the fetus. 444 Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to 445 physiologic, doses suggests that rodents are more prone to teratogenic effects from 446 corticosteroids than humans. In addition, because there is a natural increase in corticosteroid 447 production during pregnancy, most women will require a lower exogenous corticosteroid dose 448 and many will not need corticosteroid treatment during pregnancy. 449 Nursing Mothers: It is not known whether fluticasone propionate is excreted in human breast 450 milk. Subcutaneous administration to lactating rats of 10 mcg/kg tritiated fluticasone propionate 451 (approximately 1/25 the maximum recommended daily inhalation dose in adults on a mcg/m2 452 basis) resulted in measurable radioactivity in milk. Because other corticosteroids are excreted in 453 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 human milk, caution should be exercised when FLOVENT ROTADISK is administered to a 454 nursing woman. 455 Pediatric Use: Two hundred fourteen (214) patients 4 to 11 years of age and 142 patients 12 to 456 16 years of age were treated with FLOVENT ROTADISK in US clinical trials. The safety and 457 effectiveness of FLOVENT ROTADISK Inhalation Powder in children below 4 years of age 458 have not been established. 459 Inhaled corticosteroids, including fluticasone propionate, may cause a reduction in growth in 460 children and adolescents (see PRECAUTIONS). If a child or adolescent on any corticosteroid 461 appears to have growth suppression, the possibility that they are particularly sensitive to this 462 effect of corticosteroids should be considered. Patients should be maintained on the lowest dose 463 of inhaled corticosteroid that effectively controls their asthma. 464 Geriatric Use: Safety data have been collected on 280 patients (FLOVENT® DISKUS® 465 N = 83, FLOVENT ROTADISK N = 197) 65 years of age or older and 33 patients (FLOVENT 466 DISKUS N = 14, FLOVENT ROTADISK N = 19) 75 years of age or older who have been 467 treated with fluticasone propionate inhalation powder in US and non-US clinical trials. There 468 were no differences in adverse reactions compared to those reported by younger patients. In 469 addition, there were no apparent differences in efficacy between patients 65 years of age or older 470 and younger patients. Fifteen patients 65 years of age or older and 1 patient 75 years of age or 471 older were included in the efficacy evaluation of US clinical studies. 472 ADVERSE REACTIONS 473 The incidence of common adverse events in Table 1 is based upon 6 placebo-controlled 474 clinical trials in which 1,384 patients ≥4 years of age (520 females and 864 males) previously 475 treated with as-needed bronchodilators and/or inhaled corticosteroids were treated with 476 FLOVENT ROTADISK (doses of 50 to 500 mcg twice daily for up to 12 weeks) or placebo. 477 478 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Table 1. Overall Adverse Events With >3% Incidence in Controlled Clinical Trials With 479 FLOVENT ROTADISK in Patients ≥4 Years Previously Receiving Bronchodilators and/or 480 Inhaled Corticosteroids 481 Adverse Event Placebo (N = 438) % FLOVENT 50 mcg Twice Daily (N = 255) % FLOVENT 100 mcg Twice Daily (N = 331) % FLOVENT 250 mcg Twice Daily (N = 176) % FLOVENT 500 mcg Twice Daily (N = 184) % Ear, nose, and throat Pharyngitis 7 6 8 8 13 Nasal congestion 5 4 4 7 7 Sinusitis 4 5 4 6 4 Rhinitis 4 4 9 2 3 Dysphonia 0 <1 4 6 4 Oral candidiasis 1 3 3 4 11 Respiratory Upper respiratory infection 13 16 17 22 16 Influenza 2 3 3 3 4 Bronchitis 2 4 2 1 2 Other Headache 11 11 9 14 15 Diarrhea 1 2 2 0 4 Back problems <1 <1 1 1 4 Fever 3 4 4 2 2 Average duration of exposure (days) 53 77 68 78 60 482 Table 1 includes all events (whether considered drug-related or nondrug-related by the 483 investigator) that occurred at a rate of over 3% in any of the groups treated with FLOVENT 484 ROTADISK and were more common than in the placebo group. In considering these data, 485 differences in average duration of exposure should be taken into account. 486 These adverse reactions were mostly mild to moderate in severity, with <2% of patients 487 discontinuing the studies because of adverse events. Rare cases of immediate and delayed 488 hypersensitivity reactions, including rash and other rare events of angioedema and 489 bronchospasm, have been reported. 490 Other adverse events that occurred in these clinical trials using FLOVENT ROTADISK with 491 an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were: 492 Ear, Nose, and Throat: Otitis media, tonsillitis, nasal discharge, earache, laryngitis, 493 epistaxis, sneezing. 494 Eye: Conjunctivitis. 495 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Gastrointestinal: Abdominal pain, viral gastroenteritis, gastroenteritis/colitis, abdominal 496 discomfort. 497 Miscellaneous: Injury. 498 Mouth and Teeth: Mouth irritation. 499 Musculoskeletal: Sprain/strain, pain in joint, disorder/symptoms of neck, muscular 500 soreness, aches and pains. 501 Neurological: Migraine, nervousness. 502 Respiratory: Chest congestion, acute nasopharyngitis, dyspnea, irritation due to inhalant. 503 Skin: Dermatitis, urticaria. 504 Urogenital: Dysmenorrhea, candidiasis of vagina, pelvic inflammatory disease, 505 vaginitis/vulvovaginitis, irregular menstrual cycle. 506 There were no clinically relevant differences in the pattern or severity of adverse events in 507 children compared with those reported in adults. 508 FLOVENT Inhalation Aerosol (660 or 880 mcg twice daily) was administered for 16 weeks 509 to patients with asthma requiring oral corticosteroids. Adverse events reported more frequently 510 in these patients compared to patients not on oral corticosteroids included sinusitis, nasal 511 discharge, oropharyngeal candidiasis, headache, joint pain, nausea and vomiting, muscular 512 soreness, malaise/fatigue, and insomnia. 513 Observed During Clinical Practice: In addition to adverse events reported from clinical 514 trials, the following events have been identified during postapproval use of fluticasone 515 propionate in clinical practice. Because they are reported voluntarily from a population of 516 unknown size, estimates of frequency cannot be made. These experiences have been chosen for 517 inclusion due to either their seriousness, frequency of reporting, or causal connection to 518 fluticasone propionate or a combination of these factors. 519 Ear, Nose, and Throat: Aphonia, facial and oropharyngeal edema, hoarseness, and throat 520 soreness and irritation. 521 Endocrine and Metabolic: Cushingoid features, growth velocity reduction in 522 children/adolescents, hyperglycemia, osteoporosis, and weight gain. 523 Eye: Cataracts. 524 Non-Site Specific: Very rare anaphylactic reaction, very rare anaphylactic reaction in 525 patients with severe milk protein allergy. 526 Psychiatry: Agitation, aggression, depression, and restlessness. 527 Respiratory: Asthma exacerbation, bronchospasm, chest tightness, cough, immediate 528 bronchospasm, paradoxical bronchospasm, pneumonia, and wheeze. 529 Skin: Contusions, ecchymoses, and pruritus. 530 Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may 531 present with systemic eosinophilic conditions, with some patients presenting with clinical 532 features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated 533 with systemic corticosteroid therapy. These events usually, but not always, have been associated 534 with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of 535 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with 536 other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, 537 vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy 538 presenting in their patients. A causal relationship between fluticasone propionate and these 539 underlying conditions has not been established (see PRECAUTIONS: Eosinophilic Conditions). 540 OVERDOSAGE 541 Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS). 542 Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate 543 inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate inhalation 544 aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at doses of 545 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. 546 Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 547 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or 548 moderate severity, and incidences were similar in active and placebo treatment groups. The oral 549 and subcutaneous median lethal doses in mice and rats were >1,000 mg/kg (>2,000 and >4,100 550 times, respectively, the maximum recommended daily inhalation dose in adults and >9,600 and 551 >19,000 times, respectively, the maximum recommended daily inhalation dose in children on a 552 mg/m2 basis). 553 DOSAGE AND ADMINISTRATION 554 FLOVENT ROTADISK should be administered by the orally inhaled route in patients 4 555 years of age and older. Individual patients will experience a variable time to onset and degree of 556 symptom relief. Generally, FLOVENT ROTADISK has a relatively rapid onset of action for an 557 inhaled corticosteroid. Improvement in asthma control following inhaled administration of 558 fluticasone propionate can occur within 24 hours of beginning treatment, although maximum 559 benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. 560 After asthma stability has been achieved (see Table 2), it is always desirable to titrate to the 561 lowest effective dosage to reduce the possibility of side effects. Dosages as low as 50 mcg twice 562 daily have been shown to be effective in some patients. For patients who do not respond 563 adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide 564 additional asthma control. The safety and efficacy of FLOVENT ROTADISK when 565 administered in excess of recommended dosages have not been established. 566 Rinsing the mouth after inhalation is advised. 567 The recommended starting dosage and the highest recommended dosage of FLOVENT 568 ROTADISK, based on prior anti-asthma therapy, are listed in Table 2. 569 570 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Table 2. Recommended Dosages of FLOVENT ROTADISK 571 Previous Therapy Recommended Starting Dosage Highest Recommended Dosage Adults and Adolescents Bronchodilators alone 100 mcg twice daily 500 mcg twice daily Inhaled corticosteroids 100-250 mcg twice daily* 500 mcg twice daily Oral corticosteroids† 1,000 mcg twice daily‡ 1,000 mcg twice daily‡ Children 4 to 11 Years Bronchodilators alone 50 mcg twice daily 100 mcg twice daily Inhaled corticosteroids 50 mcg twice daily 100 mcg twice daily * Starting dosages above 100 mcg twice daily for adults and adolescents and 50 mcg twice daily 572 for children 4 to 11 years of age may be considered for patients with poorer asthma control or 573 those who have previously required doses of inhaled corticosteroids that are in the higher 574 range for that specific agent. 575 NOTE: In all patients, it is desirable to titrate to the lowest effective dosage once asthma 576 stability is achieved. 577 † For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone 578 should be reduced no faster than 2.5 mg/day on a weekly basis, beginning after at least 579 1 week of therapy with FLOVENT ROTADISK. Patients should be carefully monitored for 580 signs of asthma instability, including serial objective measures of airflow, and for signs of 581 adrenal insufficiency (see WARNINGS). Once prednisone reduction is complete, the dosage 582 of fluticasone propionate should be reduced to the lowest effective dosage. 583 ‡ This dosing recommendation is based on clinical data from a study conducted using 584 FLOVENT Inhalation Aerosol. No clinical trials have been conducted in patients on oral 585 corticosteroids using FLOVENT ROTADISK; no direct assessment of the clinical 586 comparability of equal nominal doses for FLOVENT ROTADISK and FLOVENT Inhalation 587 Aerosol in this population has been conducted. 588 589 Geriatric Use: In studies where geriatric patients (65 years of age or older, see 590 PRECAUTIONS) have been treated with FLOVENT ROTADISK, efficacy and safety did not 591 differ from that in younger patients. Consequently, no dosage adjustment is recommended. 592 Directions for Use: Illustrated Patient’s Instructions for Use accompany each package of 593 FLOVENT ROTADISK. 594 HOW SUPPLIED 595 FLOVENT ROTADISK 50 mcg is a circular double-foil pack containing 4 blisters of the 596 drug. Fifteen (15) ROTADISKS are packaged in a white polypropylene tube, and the tube is 597 packaged in a plastic-coated, moisture-protective foil pouch. A carton contains the foil pouch of 598 15 ROTADISKS and 1 dark orange and peach DISKHALER inhalation device (NDC 0173- 599 0511-00). 600 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 FLOVENT ROTADISK 100 mcg is a circular double-foil pack containing 4 blisters of the 601 drug. Fifteen (15) ROTADISKS are packaged in a white polypropylene tube, and the tube is 602 packaged in a plastic-coated, moisture-protective foil pouch. A carton contains the foil pouch of 603 15 ROTADISKS and 1 dark orange and peach DISKHALER inhalation device (NDC 0173- 604 0509-00). 605 FLOVENT ROTADISK 250 mcg is a circular double-foil pack containing 4 blisters of the 606 drug. Fifteen (15) ROTADISKS are packaged in a white polypropylene tube, and the tube is 607 packaged in a plastic-coated, moisture-protective foil pouch. A carton contains the foil pouch of 608 15 ROTADISKS and 1 dark orange and peach DISKHALER inhalation device (NDC 0173- 609 0504-00). 610 Store at controlled room temperature (see USP), 20° to 25°C (68° to 77°F) in a dry place. 611 Keep out of reach of children. Do not puncture any fluticasone propionate ROTADISK 612 blister until taking a dose using the DISKHALER. 613 Use the ROTADISK blisters within 2 months after opening of the moisture-protective 614 foil overwrap or before the expiration date, whichever comes first. Place the sticker 615 provided with the product on the tube and enter the date the foil overwrap is opened and 616 the 2-month use date. 617 618 619 620 GlaxoSmithKline 621 Research Triangle Park, NC 27709 622 623 ©Year, GlaxoSmithKline. All rights reserved. 624 625 Month Year RL- 626 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FLOVENT ® ROTADISK® 50 mcg (fluticasone propionate inhalation powder, 50 mcg) FLOVENT ® ROTADISK® 100 mcg (fluticasone propionate inhalation powder, 100 mcg) FLOVENT ® ROTADISK® 250 mcg (fluticasone propionate inhalation powder, 250 mcg) Please read this leaflet carefully before you start to take your medicine. It provides a summary of information on your medicine. For further information ask your doctor or pharmacist. Your doctor has prescribed FLOVENT ROTADISK 50 mcg, FLOVENT ROTADISK 100 mcg, or FLOVENT ROTADISK 250 mcg. Each ROTADISK®contains a medicine called fluticasone propionate, which is a synthetic corticosteroid. Corticosteroids are natural substances found in the body that help fight inflammation. They are used to treat asthma because they reduce the swelling and irritation in the walls of the small air passages in the lungs and ease breathing problems. When inhaled regularly, corticosteroids also help to prevent attacks of asthma. 1. MAKE SURE that this medicine is suitable for you (see “Before Using Your FLOVENT ROTADISK” below). 2. It is important that you inhale each dose as your doctor has advised. If you are not sure, ask your doctor or pharmacist. 3. Use your ROTADISK as directed by your doctor. DO NOT STOP THE TREATMENT EVEN IF YOU FEEL BETTER unless told to do so by your doctor. 4. DO NOT inhale more doses or use the ROTADISK more often than instructed by your doctor. 5. This medicine is NOT intended to provide rapid relief of your breathing difficulties during an asthma attack. It must be taken at regular intervals as recommended by your doctor, and not as an emergency measure. 6. Your doctor may prescribe additional medicine (such as bronchodilators) for emergency relief if an acute asthma attack occurs. Please contact your doctor if: • an asthma attack does not respond to the additional medicine • you require more of the additional medicine than usual. 7. If you also use another medicine by inhalation, you should consult your doctor for instructions on when to use it in relation to using FLOVENT ROTADISK. TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDICINE: • If you are pregnant (or intending to become pregnant), • If you are breastfeeding a baby, • If you are allergic to FLOVENT ROTADISK, any other medicines, or food products. In some circumstances, this medicine may not be suitable and your doctor may wish to give you a different medicine. Make sure that your doctor knows what other medicines you are taking. • If you are taking a medicine containing ritonavir (commonly used to treat HIV infection or AIDS). • Follow the instructions below. If you have any problems, tell your doctor or pharmacist. • It is important that you inhale each dose as directed by your doctor. The label will usually tell you what dose to take and how often. If it doesn’t, or you are not sure, ask your doctor or pharmacist. DOSAGE • Use as directed by your doctor. • It is VERY IMPORTANT that you follow your doctor’s instructions as to how many inhalations to inhale and how often to use your FLOVENT ROTADISK. • DO NOT inhale more doses or use your FLOVENT ROTADISK more often than your doctor advises. • It may take 1 to 2 weeks or longer for this medicine to work and it is VERY IMPORTANT THAT YOU USE IT REGULARLY. DO NOT STOP TREATMENT EVEN IF YOU ARE FEELING BETTER unless told to do so by your doctor. • If you miss a dose, just take your regularly scheduled next dose when it is due. DO NOT DOUBLE the dose. This leaflet shows you how to use FLOVENT ROTADISK. The medicine comes in small circular foil disks. There are 4 blisters around the edge of each disk, and these blisters each contain a measured dose of your medicine as a powder that you breathe by using a specially designed plastic device called the DISKHALER®. The medicine is available in several different strengths, and your doctor has chosen the one most suitable for you. The DISKHALER has a number of parts: 1. outer body with a hinged lid and piercing needle 2. cleaning brush that fits into a space at the rear of the body 3. mouthpiece cover 4. white wheel on which the disk is placed 5. white sliding tray with mouthpiece fitted to the wheel 6. foil disk 1. Remove the mouthpiece cover and check to make sure that the mouthpiece is clean (see Figure 1). Inspect the mouthpiece for the presence of foreign objects before each use. 2. Hold the corners of the white tray and pull out gently until you can see all the plastic ridges on the sides of the tray (see Figure 2). 3. Put your finger and thumb on the ridges, squeeze inward, and gently pull the tray out of the body of the DISKHALER (see Figure 3). 4. Place a disk on the wheel with the numbers facing up, and then slide the tray back into the DISKHALER (see Figure 4). Patient’s Instructions for Use Loading a Disk into the DISKHALER® What You Should Know About FLOVENT®ROTADISK® Before Using Your FLOVENT ROTADISK Using Your FLOVENT ROTADISK How to Use Your FLOVENT ROTADISK 2 1 4 5 3 Figure 1 Figure 2 Figure 3 Figure 4 6 Important Points to Remember About FLOVENT ROTADISK This label may not be the latest approved by FDA. or current labeling information, please visit https://www.fda.gov/drugsatfd 5. Hold the corners of the tray (see Figure 5) and slide the tray out and in. This will rotate the disk. 6. Continue until the number “4” appears in the small window (see Figure 6). The disk is now ready for use. As you use each dose, the number of doses remaining is shown in the window. 7. Keep the DISKHALER level. Lift up the back of the lid as far as it will go until it is fully upright (see Figure 7). (IMPORTANT: The lid must be raised until fully upright to pierce both the top and bottom of the blister.) Then close the lid. The DISKHALER is now ready for use. 8. Breathe out as far as comfortable (see Figure 8). 9. Keep the DISKHALER level and raise it to your mouth. Place the mouthpiece between your teeth and close your lips firmly around it but do not bite down on it (see Figure 9). Do not cover the small air holes on either side of the mouthpiece. 10. Breathe in through your mouth steadily and as deeply as you can. 11. Hold your breath and remove the DISKHALER from your mouth (see Figure 10). Continue to hold your breath for up to 10 seconds or as long as is comfortable. 12. Turn the disk to the next number (“3”) by gently pulling out the tray and pushing it in once (see Figure 11). Do not pierce the blister until you are ready to take the next dose. When you need to take another dose, repeat steps 7 through 12. Always replace the mouthpiece cover after use. Each disk has 4 blisters. As you use up each blister, the blister numbers appearing in the small window of the tray will count backwards (i.e., “4”, “3”, “2”, “1”). When the number “4” reappears after you have taken 4 inhalations from the DISKHALER, the disk is empty and should be replaced. To take out the old disk and put in the new one, repeat steps 2 through 4. Clean your DISKHALER at least once a week as follows: 1. Remove the tray from the body of the DISKHALER. 2. Hold the wheel between your forefinger and thumb and pull upwards to separate it from the tray. 3. There is a brush in the small space under the lid at the rear of the body of the DISKHALER. Brush away any powder left behind on the parts of the DISKHALER. 4. Replace the wheel and push it down firmly until it snaps into place. 5. Replace the tray and mouthpiece cover. You may also separate the parts of the DISKHALER as described above and rinse them with warm water. Let the parts air dry before putting back together. • Keep out of reach of children. • Store at 20° to 25°C (68° to 77°F) in a dry place. • Use the ROTADISK blisters within 2 months after opening of the moisture-protective foil overwrap or before the expiration date, whichever comes first. Place the sticker provided with the product on the tube containing the ROTADISK blisters and fill in the date you opened the foil overwrap and the 2-month use date. • Do not puncture any fluticasone propionate ROTADISK blister until taking a dose using the DISKHALER. REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT give this medicine to anyone else. This leaflet does not contain the complete information about your medicine. If you have any questions, or are not sure about something, then you should ask your doctor or pharmacist. You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine. Your doctor has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR DOCTOR. If you have any questions about alternatives, consult with your doctor. GlaxoSmithKline Research Triangle Park, NC 27709 ©2003, GlaxoSmithKline. All rights reserved. July 2003 RL-2023 Getting Ready for the Next Dose Replacing the Disk When it is Empty Cleaning Your DISKHALER Storing Your FLOVENT ROTADISK FURTHER INFORMATION Getting Ready for the First Dose Opening the Blister to Release a Dose Inhaling Your Medicine Figure 5 Figure 7 Figure 8 Figure 9 Figure 10 Figure 6 Figure 11 This label may not be the latest approved by FDA. or current labeling information, please visit https://www.fda.gov/drugsatfd	custom-source	2025-02-12T13:46:46.863569	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20549slr016,20548slr020,20121slr030_flonase_lbl.pdf', 'application_number': 20121, 'submission_type': 'SUPPL ', 'submission_number': 30}
12,231	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all of the information needed to use OMNISCAN safely and effectively. See fulI prescribing information for OMNISCAN. OMNISCAN™ (gadodiamide) Injection for Intravenons Use Initial U.S. Approval: 1993 WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) See full prescribing information for complete boxed warning. NOT FOR INTRATHECAL USE . Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits (5.4). NSF . Gadolinium-based contrast agents (GBCAs) increase risk ofNSF in patients with (5.2): o acute or chronic severe renal insuffciency (glomerular filtration rate ~ 30 mLlmin/1.73m2), or o acute renal insuffciency of any severity due to hepato-renal syndrome or in perioperative liver transplantation period. . In these patients, avoid use of GBCAs unless diagnostic information is essential and not available with non-contrast enhanced MRI (5.2). . NSF may result in fatal or debiltating systemic fibrosis affecting the skin, muscle, and internal orrmns (5.2). -------------------------- RECENT MAJOR CHAN G ES--------------------------- Boxed Warning: Nephrogenic Systemic Fibrosis (NSF) 9/2007 Warnings and Precautions: Hypersensitivity Reactions (5.1) 9/2007 Warnings and Precautions: NSF (5,2) 9/2007 Warnings and Precautions: Acute Renal Failure (5.3) 9/2007 Warnings and Precautions: Not for Intrathecal Use (5.4) 9/2007 ----------m-m----------INDICA TIONS AND USAGEm----------------------- OMNISCAN is a gadolinium-based contrast agent for diagnostic magnetic resonance imaging (MRI) indicated for intravenous use to: . Visualize lesions with abnormal vascularity in the brain, spine, and associated tissues (1.) . Facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space (1,2) ________________n_____ DOSAGE AND AD MINISTRA TI ON ------"--------------- . CNS - Adults and Pediatrics; 2-16 years of age: 0,2 mL/kg (0.1 mmol/kg) (2.1,2.4) . Body - Adults and Pediatrics; 2-16 years of age: Kidney: 0.1 mL/kg (0.05 mmol/kg) Intrathoracic, intra-abdominal, and pelvic cavities: 0,2 mL/kg (0.1 mmol/g) (2.2, 2.4) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Sterile aqueous solution for intravenous injection; 287 mglmL (3) -------------------------------CO NTRAIND I CA TI ONS------------------------------ None (4) --------------------- W ARNIN GS AND PRECA UTI ONS-------------------m-- . Anaphylactoid and other serious hypersensitivity reactions including fatal reactions have occurred paricularly in patients with history of allergy or drug reactions, Monitor patients closely for need of emergency cardiorespiratory support (5.1). . Nephrogenic Systemic Fibrosis (NSF) has occurred in patients with severe renal insuffciency, Higher than recommended dosing or repeat dosing appears to increase the risk (5.2). . Acute renal failure has occurred in patients with preexisting renal insuffciency. Use the lowest necessary dose of OMNISCAN and evaluate renal function in these patients (5.3). ----------------------------AD VERSE REA CTI 0 NS------------------------m--- . The most frequent adverse reactions (S 3%) observed during OMNISCAN adult clinical studies were nausea, headache, and dizziness (6.1) . Serious or life-threatening reactions include: cardiac failure, arrhythmia and myocardial infarction (6.1, 6.3) To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-I088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: month/yr FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: NOT FOR INTRA THECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) 1 INDICATIONS AND USAGE 1, i CNS (Central Nervous System) 1,2 Body (Intrathoracic (noncardiac), Intra-abdominal, Pelvic and Retroperitoneal Regions) 2 DOSAGE AND ADMINISTRATION 2, i CNS (Central Nervous System) 2.2 Body (Intrathoracic (noncardiac), Intra-abdominal, Pelvic and Retroperitoneal Regions) 2.3 Dosage Chart 2.4 Dosing.Guidelines 2.5 Repeat Dosing 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICA TIONS 5 WARNINGS AND PRECAUTIONS s. i Hypersensitivity Reactions 5,2 Nephrogenic Systemic Fibrosis 5.3 Acute Renal Failure 5,4 Not for Intrathecal Use 5,5 Impaired Visualization of Lesions Detectable with Non-contrast MRI 5,6 Laboratory Test Findings 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience (Adults) 6.2 Clinical Studies Experience (Pediatrics) 6.3 Postmarketing Experience . 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal/Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12,2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14, i CNS (Central Nervous System) 14,2 Body (Intrathoracic (noncardiac), Intra-abdominal, Pelvic and Retroperitoneal Regions) . 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 'Sections or subsections omitted from the full prescribing information are not listed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) NOT FOR INTRA THECAL USE Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits (see Warnings and Precautions (5.4)/. NSF Gadolinium-based contrast agents increase the risk for NSF in patients with: . acute or chronic severe renal insuffciency (glomenilar fitration rate ~ 30 mL/min/1.73m2), or . acute renal insuffciency of any severity due to the hepato-renal syndrome or in the peri operative liver transplantation period. In these patitnts, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debiltating systemic fibrosis affecting the skin, muscle, and internal organs. Screen all patients for renal dysfunction by obtaining a history and laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a suffcient period of time for elimination of the agent from the body prior to any readministration (see Warnings and Precautions (5.2)). INDICATIONS AND USAGE 1. CNS (Central Nervous System) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues (see Clinical Studies (14.1)). 1.2 Body (Intrathoracic (noncardiac). Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space (see Clinical Studies (14.2)). 2 DOSAGE AND ADMINISTRATION 2.1 CNS (Central Nervous System) Adults: The recommended dose of OMNISCAN is 0,2 mLlkg (0.1 mmol/kg) administered as a bolus intravenous injection. An additional 0.4 mLlkg (0.2 mmol/kg) can be given within 20 minutes of the first dose (see Dosage and Administration (2,3)). Pediatric Patients (2-16 years): The recommended dose of OMNISCAN is 0.2 mLlkg (0.1 mmol/kg) administered as a bolus intravenous injection (see Dosage and Administration (2,3)). 2.2 Body (Intrathoracic (noncardiac), Intra-abdominal, Pelvic and Retroperitoneal Regions) Adult and Pediatric Patients (2-16years of age): For imaging the kidney, the recommended dose of OMNISCAN is 0.1 mLlkg (0,05 mmollkg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of OMNISCAN is 0.2 mLlkg (0,1 mmol/kg) (see Dosage and Administration (2.3)), 2.3 Dosage Chart BODY PEDIATRIC ADULTS WEIGHT 0.05 0.1 0.05 0.1 0.2 Kg Ib (mmol/ki:Ü (mmol/kl!) VOLUME (mL) VOLUME (mU 12 26 1. 2.4 - - - 14 31 1.4 2,8 - - - 16 35 1.6 3.2 - - - 18 40 1.8 3,6 - - - 20 44 2 4 - - - 22 48 2.2 4.4 - - - 24 53 2.4 4.8 - - - 26 57 2.6 5,2 - - - 28 62 2.8 5,6 - - - 30 66 3 6 - - - 40 88 4 8 4 8 16 SO 110 5 10 5 10 20 60 132 6 12 6 12 24 70 154 7 14 7 14 28 80 176 8 16 8 16 32 90 198 - - 9 18 36 100 220 - - 10 20 40 110 242 - - 11 22 44 120 264 - - 12 24 48 130* 286 - - 13 26 52 *The heaviest patient in clinical studies weighed 136 kg. 2.4 Dosing Guidelines Inspect OMNISCAN visually for pariculate matter and discoloration before administration, whenever solution and container permit. Do not use the solution if it is discolored or particulate matter is present. Draw OMNISCAN into the syringe and use immediately, Discard any unused portion ofOMNISCAN Injection, To ensure complete delivery of the desired volume of contrast medium, follow the injection of OMNISCAN with a 5 mL flush of 0,9% sodium chloride, as provided in the Prefill Plus needle-free system, Complete the imaging procedure within i hour of administration ofOMNISCAN. 2.5 Repeat Dosing Sequential use during the same diagnostic session has been studied in adult CNS use only, If the physician determines repeat dosing is required in non- CNS imaging in adults or pediatric patients, renal function should be nOfUal and the time interval between repeat doses should be at least 7 hours to allow for clearance of the drug from the body (see Clinical Pharmacology (12.3)), 3 DOSAGE FORMS AND STRENGTHS Sterile aqueous solution for intravenous injection; 287 mglmL. 4 CONTRA INDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Anaphylactoid and anaphylactic reactions, with cardiovascular, respiratory and/or cutaneous manifestations, resulting in death have occurred. If such a reaction occurs, stop OMNISCAN Injection and immediately begin appropriate therapy, Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after OMNISCAN Injection. 5.2 Nephrogenic Systemic Fibrosis (see Boxed Warning) Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency (glomerular filtration rate ~ 30 mLlmin/1. 73m2) and in patients with acute renal insuffciency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention ofNSF is unknown, Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impaifUent at the time of exposure. Postmarketing reports have identified the development of NSF following single and multiple administrations of gadolinium-based contrast agents, These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was gadodiamide (Omniscan™), followed by gadopentetate dimeglumine (Magnevist4!) and gadoversetamide (OptiMARK4!), NSF has also developed following sequential administrations of gadodiamide with gadobenate dimeglumine (MultiHance~ or gadoteridol (ProHance~, The number of postmarketing reports is subject to change over time and may not reflect the true proportion of cases associated with any specific gadolinium-based contrast agent. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The extent of risk for NSF following exposure to any specific gadolinium- based contrast agent is unknown and may vary among the agents. Published report are limited and predominantly estimate NSF risks with gadodiamide. In one retrospective study of 370 patients with severe renal insuffciency who received gadodiamide, the estimated risk for development ofNSF was 4% (J Am Soc NephroI2006;17:23S9). The risk, if any, for the development ofNSF among patients with mild to moderate renal insufficiency or normal renal function is unknown. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a suffcient period of time for elimination of the agent prior to any read ministration (see Clinical Pharmacology (12,2) and Dosage and Administration (2)). 5.3 Acute Renal Failure In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of OMNISCAN Injection, The risk of renal failure may increase with increasing dose of gadolinium contrast. Use the lowest necessary dose of contrast and evaluate renal function in patients with renal insuffciency, Acute renal failure was observed in ~ 1 % of patients in OMNISCAN clinical studies (see Adverse Reactions (6)). OMNISCAN is cleared by glomerular fitration. Hemodialysis also enhances OMNISCAN clearance (see Use in Spectfc Populations (8.5, 8.6)). 5.4 Not for Intrathecal Use Inadvertent intrathecal use of OMNISCAN has occurred and caused convulsions, coma, sensory and motor neurologic deficits, 5.5 Impaired Visualization of Lesions Detectable with Non-contrast MRI Pammagnetic contrast agents such w OMNISCAN might impair the visualization of lesions which are seen on the non-contrast MRL This may be due to effects of the paramagnetic contrast agent, or imaging parameters, Exercise caution when OMNISCAN MRI scans are interpreted in the absence of a companion non-contrast MRI. 5.6 Laboratory Test Findings Asymptomatic, transitory changes in serum iron have been observed. The clinical significance is unknown. OMNlSCAN interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals, resulting in serum calcium concentrations lower than the true values. In patients with normal renal function, this effect lasts for 12-24 hours, In patients with decreased renal function, the interference with calcium measurements is expected to last during the prolonged elimination of OMNISCAN, Afer patients receive OMNlSCAN, careful attention should be used in selecting the type of method used to measure calcium, 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varing conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice, 6.1 Clinical Studies Experience (Adults) In clinical studies 1160 patients were exposed to OMNISCAN, The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients, The majority of these reactions were of mild to moderate intensity, The following adverse reactions occurred in 1 % or less of patients: Application Site Disorders: Injection site reaction, Autonomic Nervous System Disorders: Vwodilation. Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope. Cardiovascular Disorders: Cardiac failure, rare arhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis. Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, parethesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine. Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena, Hearing and Vestibular Disorders: Tinnitus. Liver and Biliary System Disorders: Abnormal hepatic function. Musculoskeletal System Disorders: Arhralgia, myalgia. Respiratory System Disorders: Rhinitis, dyspnea. Skin and Appendage Disorders: Pruritus, rash, eryhematous rash, sweating increased, urticaria, Special Senses, Other Disorders: Taste loss, taste perversion. Urinary System Disorders: Acute reversible renal failure. Vision Disorders: Abnormal vision. 6.2 Clinical Studies Experience (pediatrics) In the 97 pediatric patients in CNS studies with OMNlSCAN (see Clinical Studies (14.1)) and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults. 6.3 Postmarketing Experience Because postmatketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during the postmarketing use of OMNISCAN: Nervous System Disorders: Inadvertent intrathecal use causes seizures, coma, paresthesia, paresis, General Disorders: Nephrogenic Systemic Fibrosis (NSF) (see Warnings and Precautions (5.2)). 7 DRUG INTERACTIONS Specific drug interaction studies have not been conducted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: OMNISCAN has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0,6 times the human dose based on a body surface area comparison), These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to OMNISCAN administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2,5 mmol/kg/day for IO days during gestation (1. times the maximum human dose bwed on a bogy surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2,5 mmol/kg/day cannot be made, Adequate and well controlled studies in pregnant women have not been conducted, OMNISCAN should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus, b~ 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering OMNlSCAN to a nursing woman, 8.4 Pediatric Use The safety and effcacy of OMNISCAN at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of OMNISCAN in adults, a pediatric CNS imaging study, and safety data in the scientific literature, However, the safety and effcacy of doses greater than O. 1 mmol/kg and of repeated doses have not been studied in pediatric patients. Pharmacokinetics of OMNISCAN have not been studied in pediatrics, The glomerular fitration rate of neonates and infants is much lower than that of adults. The pharacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established, 8.5 Geriatric Use In clinical studies ofOMNISCAN, 243 patients were between 65 and 80 years of age while lS were over 80, No overall differences in safety or effectiveness were observed between these patients and younger patients, Other reported clinical experience hw not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy, OMNISCAN is excreted by the kidney, and the risk of toxic reactions to OMNISCAN may be greater in patients with impaired renal function (see This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Warnings and Precautions (5,3)). Because elderly patients are more likely to have decreased renal function, select dose carefully and consider assessment of renal function before OMNISCAN use. 8.6 Renal/Hepatic Impairment Dose adjustments in renal or hepatic impairment have not been studied. Caution should be exercised in patients with impaired renal insuffciency (see Warnings and Precautions (5.2, 5.3)). 10 OVERDOSAGE Clinical consequences of overdose with OMNISCAN have not been reported, The minimum lethal dose of intravenously administered OMNISCAN in rats and mice is greater than 20 mmollkg .(200 times the recommended human dose of 0.1 mmollkg; 67 times the cumulative 0.3 mmol/kg dose), OMNISCAN is dialyzable. 11 DESCRIPTION OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging, OMNISCAN is administered by intravenous injection, OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each i mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide, OMNISCAN contains no antimicrobial preservative, OMNISCAN is a 0.5 mollL solution of aqua(S,8-bis( carboxymethyl)- i 1-(2-(methylamino )-2-oxoethyl)- 3 -oxo- 2,S,8,lI-tetraazatridecan-l3-oato (3-)-NS, N', Nil, 03, 05, 0', Oil, OlJ) gadolinium hydrate, with a molecular weight of 573,66 (anhydrous), an empirical formula of CI6H2,GdN509'xHiO, and the following structural formula: °n o ..O..___..____O.".':;G..(,./)NY\. ... .. ....... . . H ~ /,':~, .._.__.J.._ .~N ~","",/ .~ '\'\; .. - --........ 0 - \ "."" / :.\:'.- CH3 ./. ....-'. ,~/. 1.\4. ..... 'XH20 o N .0, \ ~ ,,'H H ' ~,.. 0 .. 0 H3C -~ ' Pertinent physicochemical data for OMNISCAN are noted below: PARAMETER Osmolality (mOsmol/kg water) (( 37°C Viscosity (cP) ~ 20°C (( 37°C (( 25°C ((2SoC 789 2 1.4 U4 US Density (glmL) Specific gravity OMNISCAN has an osmolality approximately 2,8 times that of plasma at 37°C and is hypertonic under conditions of use. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics In magnetic resonance imaging, visualization of normal and pathologic tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration ofthe spin-lattice or longitudinal relaxation time (T I); and variation of the spin-spin or transverse relaxation time (T2) , OMNISCAN is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent. By increasing the relaxation rate, OMNISCAN decreases both the T, and T2 relaxation times in tissues where it is distributed, At clinical doses, the effect is primarily on the T 1 relaxation time, and produces an increase in signal intensity. OMNISCAN does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e,g., cysts, mature postoperative scars), However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of OMNISCAN in lesions such as neoplasms, abscesses, and subacute infarcts, The pharmacokinetic parameters of OMNISCAN in various lesions are not known, There is 110 detectable biotransformation or decomposition of gadodiamide, 12.3 Pharmacokinetics The pharacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean:: SO) of 3.7 :: 2,7 minutes and 77,8:: 16 minutes, respectively. Gadodiamide is eliminated primarily in the urine with 95.4 :: 5.5% (mean :: SO) of the administered dose eliminated by 24 hours, The renal and plasma clearance rates of gadodiamide are nearly identical (1. and 1.8 mLlminlkg, respectively), and are similar to that of substances excreted primarily by glomerular fitration. The volume of distribution of gadodiamide (200 :: 61 mLlkg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro, Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertilty Long term animal studies have not been performed to evaluate' the carcinogenic potential of gadodiamide, The results of the following genotoxicity assays were negative: in vitro bacterial reverse mutation assay, in vitro Chinese Hampster Ovary (CHO)/Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT) forward mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay at intravenous doses of27 mmollkg (approximately 7 times the maximum human dose based on a body surface area comparison): Impairment of male or female fertility was not observed in rats after intravenous administration three times per week at the maximum dose tested of 1.0 mmol/kg (approximately 0.5 times the maximum human dose based on a body surface area comparison). 14 CLINICAL STUDIES 14.1 CNS (Central Nervous System) OMNISCAN (0. i mmollkg) contrast enhancement in CNS MRI was evident in a study of 439 adults, In a study of sequential dosing, 57 adults received OMNISCAN O. i mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmollkg). The MRls were compared blindly. In 54/56 (96%) patients, OMNISCAN contrast enhancement was evident with both the 0.1 mmollkg and cumulative 0,3 mmollkg OMNISCAN doses relative to non- contrast MRL In comparison to the non-contrast MRI, increased numbers of brain and spine lesions were noted in 42% of patients who received OMNISCAN at any dose, In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) OMNISCAN 0.1 mmollkg dose provided more diagnostic value and in 30/56 (54%) the cumulative OMNISCAN 0.3 mmollkg dose provided more diagnostic value, The usefulness of a single 0.3 mmollkg bolus in comparison to the cumulative 0.3 mmol/kg (0, i mmollkg followed by 0,2 mmollkg) has not been established, OMNISCAN as a single 0.1 mmollkg dose was evaluated in 97 pediatric patients with a mean age of 8,9 (2-18) years referred for CNS MRL Postcontrast MRI provided added diagnostic information, diagnostic confidence, and new patient management information in 76%, 67%, and 52%, respectively, of pediatrics. 14.2 Body (Intrathoracic (noncardiac), Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN was evaluated in a controlled trial of 276 patients referred for body MRL These patients had a mean age of 57 (9-88) years, Patients received 0.1 mmol/kg OMNISCAN for imaging the thorax (noncardiac), abdomen, and pelvic organs, or a dose of 0,05 mmol/kg for imaging the kidney, Pre- and post-OMNISCAN images were evaluated blindly for the degree of diagnostic value rated on a scale of "remarkably improved, improved, no change, worse, and cannot be determined," The postcontrast results showed "remarkably improved" or "improved" diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients, In a dose ranging study 258 patients referred for body MRI received OMNISCAN 0,025, 0.05, 0.1 mmollkg, The lowest effective dose of OMNISCAN for the kidney was 0,05 mmollkg. 16 HOW SUPPLIED/STORAGE AND HANDLING OMNISCAN (gadodiamide) Injection is a sterile, clear, colorless to slightly yellow, aqueous solution containing 287 mglmL of gadodiamide in rubber This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda stoppered vials and polypropylene syringes, OMNSICAN is supplied in the following sizes: 5 mL fill in 10 mL vial, box of 10 (NDC 0407-0690-05) 10 mL vial, box of 10 (NDC 0407-0690-10) 15 mL fill in 20 mL vial, box ofl 0 (NDC 0407-0690- 1 5) 20 mL vial, box of 10 (NDC 0407-0690-20) SO mL vial, box of 10 (NDC 0407-0690-55) 10 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-12) IS mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690- 17) 20 mL prefilled syringe, box of 10 (NC 0407-0690-22) Prefill Plus™ needle-free system OMNISCAN 15 mL, box of 10 (NDC 0407-0691-62) Contains: OMNISCAN 15 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% SodiumChloride Injection, USP LV. Flush Syringe Prefill Plus™ needle-free system OMNISCAN 20 mL, box of 10 (NDC 0407-0691-63) Contains: OMNISCAN 20 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP LV. Flush Syringe Protect OMNISCAN from strong daylight and direct exposure to sunlight. Do not freeze. Freezing can cause small cracks in the vials, which would compromise the sterility of the product. Do not use if the product is inadvertently frozen. Store OMNISCAN at controlled room temperature 20°_25°C (68°-77°F); excursions permitted to iso-30°C (59°_86°F) (see USPj. 17 PATIENT COUNSELING INFORMATION Patients receiving OMNISCAN should be instructed to inform their physician if they: . are pregnant or breast feeding, or . have a history of renal disease, convulsions, asthma or allergic respiratory disorders, or recent administration of gadolinium-based contrast. Gadolinium-based contrast agents increase the risk for NSF among patients with acute or chronic severe renal insuffciency or acute renal insuffciency due to the hepato-renal syndrome. This risk may increase with repetitive or higher than recommended doses of a gadolinium-based contrast agent. Instruct patients at increased risk for NSF to contact their physician if they develop burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; or muscle weakness, Distributed by GE Healthcare Inc., Princeton, NJ Manufactured by GE Healthcare AS, Oslo, Norway OMNISCAN is a trademark of GE Healthcare, GE and the GE Monogram are trademarks of General Electric Company, OptiMARKiI is a registered trademark of Mallinckrodt Inc. Magnevistil is a registered trademark of Berlex Laboratories, Inc, MultiHanceil is a registered trademark of Bracco International B.Y. ProHanceil is a registered trademark of Bracco Diagnostics Inc, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:46.915367	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020123s035lbl.pdf', 'application_number': 20123, 'submission_type': 'SUPPL ', 'submission_number': 35}
12,232	_______________________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all of the information needed to use OMNISCAN safely and effectively. See full prescribing information for OMNISCAN. OMNISCANTM (gadodiamide) Injection for Intravenous Use Initial U.S. Approval: 1993 WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) See full prescribing information for complete boxed warning. NOT FOR INTRATHECAL USE: • Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits (5.1). NSF: Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. • Do not administer OMNISCAN to patients with: ○ chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or ○ acute kidney injury (4). • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g., age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.2). ---------------------------RECENT MAJOR CHANGES--------------------------- Boxed Warning X/2010 Dosage and Administration (2.1, 2.5) X/2010 Contraindications (4) X/2010 Warnings and Precautions (5.2) X/2010 Patient Counseling Information (17) X/2010 ----------------------------INDICATIONS AND USAGE--------------------------- OMNISCAN is a gadolinium-based contrast agent for diagnostic magnetic resonance imaging (MRI) indicated for intravenous use to: • Visualize lesions with abnormal vascularity in the brain, spine, and associated tissues (1.1) • Facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space (1.2) -----------------------DOSAGE AND ADMINISTRATION----------------------- • CNS – Adults and Pediatrics; 2-16 years of age: 0.2 mL/kg (0.1 mmol/kg) (2.1, 2.4) • Body – Adults and Pediatrics; 2-16 years of age: Kidney: 0.1 mL/kg (0.05 mmol/kg) Intrathoracic, intra-abdominal, and pelvic cavities: 0.2 mL/kg (0.1 mmol/kg) (2.2, 2.4) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- Sterile aqueous solution for intravenous injection; 287 mg/mL (3) -------------------------------CONTRAINDICATIONS------------------------------ Patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) or acute kidney injury (4). -----------------------WARNINGS AND PRECAUTIONS----------------------- • Nephrogenic Systemic Fibrosis (NSF) has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appears to increase the risk (5.2). • Anaphylactoid and other serious hypersensitivity reactions including fatal reactions have occurred particularly in patients with history of allergy or drug reactions. Monitor patients closely for need of emergency cardiorespiratory support (5.3). • Acute renal failure has occurred in patients with preexisting renal insufficiency. Use the lowest necessary dose of OMNISCAN and evaluate renal function in these patients (5.4). ------------------------------ADVERSE REACTIONS------------------------------- • The most frequent adverse reactions (≤ 3%) observed during OMNISCAN adult clinical studies were nausea, headache, and dizziness (6.1) • Serious or life-threatening reactions include: cardiac failure, arrhythmia and myocardial infarction (6.1, 6.3) To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2010 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) 1 INDICATIONS AND USAGE 1.1 CNS (Central Nervous System) 1.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 2 DOSAGE AND ADMINISTRATION 2.1 CNS (Central Nervous System) 2.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 2.3 Dosage Chart 2.4 Dosing Guidelines 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Not for Intrathecal Use 5.2 Nephrogenic Systemic Fibrosis 5.3 Hypersensitivity Reactions 5.4 Acute Renal Failure 5.5 Impaired Visualization of Lesions Detectable with Non-contrast MRI 5.6 Laboratory Test Findings 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience (Adults) 6.2 Clinical Studies Experience (Pediatrics) 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal/Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 CNS (Central Nervous System) 14.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 2881213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) NOT FOR INTRATHECAL USE: Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits [see Warnings and Precautions (5.1)]. NSF: • Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. • Do not administer OMNISCAN to patients with: ○ chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or ○ acute kidney injury [see Contraindications (4)]. • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g., age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. • Do not exceed the recommended OMNISCAN dose and allow a sufficient period of time for elimination of the drug from the body prior to any readministration [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 CNS (Central Nervous System) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues [see Clinical Studies (14.1)]. 1.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 CNS (Central Nervous System) Adults: The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. Pediatric Patients (2-16 years): The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection [see Dosage and Administration (2.3)]. 2.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) Adult and Pediatric Patients (2-16 years of age): For imaging the kidney, the recommended dose of OMNISCAN is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) [see Dosage and Administration (2.3)]. 2.3 Dosage Chart BODY WEIGHT kg lb PEDIATRIC 0.05 0.1 (mmol/kg) ADULTS 0.05 0.1 (mmol/kg) VOLUME (mL) VOLUME (mL) 12 26 1.2 2.4 - - 14 31 1.4 2.8 - - 16 35 1.6 3.2 - - 18 40 1.8 3.6 - - 20 44 2 4 - - 22 48 2.2 4.4 - - 24 53 2.4 4.8 - - 26 57 2.6 5.2 - - 28 62 2.8 5.6 - - 30 66 3 6 - - Reference ID: 2881213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 40 88 4 8 4 8 50 110 5 10 5 10 60 132 6 12 6 12 70 154 7 14 7 14 80 176 8 16 8 16 90 198 - - 9 18 100 220 - - 10 20 110 242 - - 11 22 120 264 - - 12 24 130 286 - - 13 26 *The heaviest patient in clinical studies weighed 136 kg. 2.4 Dosing Guidelines Inspect OMNISCAN visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not use the solution if it is discolored or particulate matter is present. Draw OMNISCAN into the syringe and use immediately. Discard any unused portion of OMNISCAN Injection. To ensure complete delivery of the desired volume of contrast medium, follow the injection of OMNISCAN with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of OMNISCAN. 3 DOSAGE FORMS AND STRENGTHS Sterile aqueous solution for intravenous injection; 287 mg/mL. 4 CONTRAINDICATIONS OMNISCAN is contraindicated in patients with: • chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or • acute kidney injury. 5 WARNINGS AND PRECAUTIONS 5.1 Not for Intrathecal Use Inadvertent intrathecal use of OMNISCAN has occurred and caused convulsions, coma, sensory and motor neurologic deficits. 5.2 Nephrogenic Systemic Fibrosis Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. Do not administer OMNISCAN to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following OMNISCAN administration to GE Healthcare (1-800-654-0118) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. When administering OMNISCAN, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to any readministration [see Boxed Warning, Contraindications (4), Clinical Pharmacology (12.2) and Dosage and Administration (2)]. 5.3 Hypersensitivity Reactions Anaphylactoid and anaphylactic reactions, with cardiovascular, respiratory and/or cutaneous manifestations, resulting in death have occurred. If such a reaction occurs, stop OMNISCAN Injection and immediately begin appropriate therapy. Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after OMNISCAN Injection. Reference ID: 2881213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.4 Acute Renal Failure In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of OMNISCAN Injection. The risk of renal failure may increase with increasing dose of gadolinium contrast. Use the lowest necessary dose of contrast and evaluate renal function in patients with renal insufficiency. Acute renal failure was observed in < 1% of patients in OMNISCAN clinical studies [see Adverse Reactions (6)]. OMNISCAN is cleared by glomerular filtration. Hemodialysis also enhances OMNISCAN clearance [see Use in Specific Populations (8.5, 8.6)]. 5.5 Impaired Visualization of Lesions Detectable with Non-contrast MRI Paramagnetic contrast agents such as OMNISCAN might impair the visualization of lesions which are seen on the non-contrast MRI. This may be due to effects of the paramagnetic contrast agent, or imaging parameters. Exercise caution when OMNISCAN MRI scans are interpreted in the absence of a companion non-contrast MRI. 5.6 Laboratory Test Findings Asymptomatic, transitory changes in serum iron have been observed. The clinical significance is unknown. OMNISCAN interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals, resulting in serum calcium concentrations lower than the true values. In patients with normal renal function, this effect lasts for 12-24 hours. In patients with decreased renal function, the interference with calcium measurements is expected to last during the prolonged elimination of OMNISCAN. After patients receive OMNISCAN, careful attention should be used in selecting the type of method used to measure calcium. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Clinical Studies Experience (Adults) In clinical studies 1160 patients were exposed to OMNISCAN. The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. The majority of these reactions were of mild to moderate intensity. The following adverse reactions occurred in 1% or less of patients: Application Site Disorders: Injection site reaction. Autonomic Nervous System Disorders: Vasodilation. Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope. Cardiovascular Disorders: Cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis. Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, paresthesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine. Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena. Hearing and Vestibular Disorders: Tinnitus. Liver and Biliary System Disorders: Abnormal hepatic function. Musculoskeletal System Disorders: Arthralgia, myalgia. Respiratory System Disorders: Rhinitis, dyspnea. Skin and Appendage Disorders: Pruritus, rash, erythematous rash, sweating increased, urticaria. Special Senses, Other Disorders: Taste loss, taste perversion. Urinary System Disorders: Acute reversible renal failure. Vision Disorders: Abnormal vision. 6.2 Clinical Studies Experience (Pediatrics) In the 97 pediatric patients in CNS studies with OMNISCAN [see Clinical Studies (14.1)] and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults. 6.3 Postmarketing Experience Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during the postmarketing use of OMNISCAN: Nervous System Disorders: Inadvertent intrathecal use causes seizures, coma, paresthesia, paresis. General Disorders: Nephrogenic Systemic Fibrosis (NSF) [see Warnings and Precautions (5.2)]. 7 DRUG INTERACTIONS Specific drug interaction studies have not been conducted. Reference ID: 2881213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: OMNISCAN has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to OMNISCAN administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. Adequate and well controlled studies in pregnant women have not been conducted. OMNISCAN should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering OMNISCAN to a nursing woman. 8.4 Pediatric Use The safety and efficacy of OMNISCAN at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of OMNISCAN in adults, a pediatric CNS imaging study, and safety data in the scientific literature. However, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients. Pharmacokinetics of OMNISCAN have not been studied in pediatrics. The glomerular filtration rate of neonates and infants is much lower than that of adults. The pharmacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established. 8.5 Geriatric Use In clinical studies of OMNISCAN, 243 patients were between 65 and 80 years of age while 15 were over 80. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. OMNISCAN is excreted by the kidney, and the risk of toxic reactions to OMNISCAN is greater in patients with impaired renal function [see Warnings and Precautions (5.2, 5.4)]. Because elderly patients are more likely to have decreased renal function, select dose carefully and assess eGFR by laboratory testing before OMNISCAN use. 8.6 Renal/Hepatic Impairment Dose adjustments in renal or hepatic impairment have not been studied. Caution should be exercised in patients with impaired renal insufficiency [see Warnings and Precautions (5.2, 5.4)]. 10 OVERDOSAGE Clinical consequences of overdose with OMNISCAN have not been reported. The minimum lethal dose of intravenously administered OMNISCAN in rats and mice is greater than 20 mmol/kg (200 times the recommended human dose of 0.1 mmol/kg; 67 times the cumulative 0.3 mmol/kg dose). OMNISCAN is dialyzable. 11 DESCRIPTION OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection. OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl) 11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9•xH2O, and the following structural formula: Reference ID: 2881213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Pertinent physicochemical data for OMNISCAN are noted below: PARAMETER Osmolality (mOsmol/kg water) @ 37°C 789 Viscosity (cP) @ 20°C 2 @ 37°C 1.4 Density (g/mL) @ 25°C 1.14 Specific gravity @ 25°C 1.15 OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics In magnetic resonance imaging, visualization of normal and pathologic tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2). OMNISCAN is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent. By increasing the relaxation rate, OMNISCAN decreases both the T1 and T2 relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity. OMNISCAN does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e.g., cysts, mature postoperative scars). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of OMNISCAN in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of OMNISCAN in various lesions are not known. There is no detectable biotransformation or decomposition of gadodiamide. 12.3 Pharmacokinetics The pharmacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean ± SD) of 3.7 ± 2.7 minutes and 77.8 ± 16 minutes, respectively. Gadodiamide is eliminated primarily in the urine with 95.4 ± 5.5% (mean ± SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200 ± 61 mL/kg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro. Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term animal studies have not been performed to evaluate the carcinogenic potential of gadodiamide. The results of the following genotoxicity assays were negative: in vitro bacterial reverse mutation assay, in vitro Chinese Hamster Ovary (CHO)/Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT) forward mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay at intravenous doses of 27 mmol/kg (approximately 7 times the maximum human dose based on a body surface area comparison). Impairment of male or female fertility was not observed in rats after intravenous administration three times per week at the maximum dose tested of 1.0 mmol/kg (approximately 0.5 times the maximum human dose based on a body surface area comparison). 14 CLINICAL STUDIES Reference ID: 2881213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14.1 CNS (Central Nervous System) OMNISCAN (0.1 mmol/kg) contrast enhancement in CNS MRI was evident in a study of 439 adults. In a study of sequential dosing, 57 adults received OMNISCAN 0.1 mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmol/kg). The MRIs were compared blindly. In 54/56 (96%) patients, OMNISCAN contrast enhancement was evident with both the 0.1 mmol/kg and cumulative 0.3 mmol/kg OMNISCAN doses relative to non-contrast MRI. In comparison to the non-contrast MRI, increased numbers of brain and spine lesions were noted in 42% of patients who received OMNISCAN at any dose. In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) OMNISCAN 0.1 mmol/kg dose provided more diagnostic value and in 30/56 (54%) the cumulative OMNISCAN 0.3 mmol/kg dose provided more diagnostic value. The usefulness of a single 0.3 mmol/kg bolus in comparison to the cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) has not been established. OMNISCAN as a single 0.1 mmol/kg dose was evaluated in 97 pediatric patients with a mean age of 8.9 (2-18) years referred for CNS MRI. Postcontrast MRI provided added diagnostic information, diagnostic confidence, and new patient management information in 76%, 67%, and 52%, respectively, of pediatrics. 14.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN was evaluated in a controlled trial of 276 patients referred for body MRI. These patients had a mean age of 57 (9-88) years. Patients received 0.1 mmol/kg OMNISCAN for imaging the thorax (noncardiac), abdomen, and pelvic organs, or a dose of 0.05 mmol/kg for imaging the kidney. Pre- and post-OMNISCAN images were evaluated blindly for the degree of diagnostic value rated on a scale of “remarkably improved, improved, no change, worse, and cannot be determined.” The postcontrast results showed “remarkably improved” or “improved” diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients. In a dose ranging study 258 patients referred for body MRI received OMNISCAN 0.025, 0.05, 0.1 mmol/kg. The lowest effective dose of OMNISCAN for the kidney was 0.05 mmol/kg. 16 HOW SUPPLIED/STORAGE AND HANDLING OMNISCAN (gadodiamide) Injection is a sterile, clear, colorless to slightly yellow, aqueous solution containing 287 mg/mL of gadodiamide in rubber stoppered vials and polypropylene syringes. OMNSICAN is supplied in the following sizes: 5 mL fill in 10 mL vial, box of 10 (NDC 0407-0690-05) 10 mL vial, box of 10 (NDC 0407-0690-10) 15 mL fill in 20 mL vial, box of 10 (NDC 0407-0690-15) 20 mL vial, box of 10 (NDC 0407-0690-20) 50 mL vial, box of 10 (NDC 0407-0690-55) 10 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-12) 15 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-17) 20 mL prefilled syringe, box of 10 (NDC 0407-0690-22) Prefill Plus™ needle-free system OMNISCAN 15 mL, box of 10 (NDC 0407-0691-62) Contains: OMNISCAN 15 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe Prefill Plus™ needle-free system OMNISCAN 20 mL, box of 10 (NDC 0407-0691-63) Contains: OMNISCAN 20 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe Protect OMNISCAN from strong daylight and direct exposure to sunlight. Do not freeze. Freezing can cause small cracks in the vials, which would compromise the sterility of the product. Do not use if the product is inadvertently frozen. Store OMNISCAN at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP]. 17 PATIENT COUNSELING INFORMATION Patients receiving OMNISCAN should be instructed to inform their physician if they: • are pregnant or breast feeding, or • have a history of renal and/or liver disease, convulsions, asthma or allergic respiratory disorders, or recent administration of gadolinium-based contrast. GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF: • Describe the clinical manifestations of NSF • Describe procedures to screen for the detection of renal impairment Instruct the patients to contact their physician if they develop signs or symptoms of NSF following OMNISCAN administration such Reference ID: 2881213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; or muscle weakness. Distributed by GE Healthcare Inc., Princeton, NJ Manufactured by GE Healthcare AS, Oslo, Norway OMNISCAN is a trademark of GE Healthcare. GE and the GE Monogram are trademarks of General Electric Company. Reference ID: 2881213 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:46.997112	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020123s037lbl.pdf', 'application_number': 20123, 'submission_type': 'SUPPL ', 'submission_number': 37}
12,234	ACCURETIC™ (quinapril HCl/hydrochlorothiazide) Tablets USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ACCURETIC should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality. DESCRIPTION ACCURETIC is a fixed-combination tablet that combines an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride, and a thiazide diuretic, hydrochlorothiazide. Quinapril hydrochloride is chemically described as [3S-[2[R(R)], 3R*]]-2-[2-[[1 (ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3 isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5. HCl and its structural formula is: Structural Formula Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hydrochlorothiazide is chemically described as: 6-Chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8CIN3O4S2 and its structural formula is: Structural Formula Hydrochlorothiazide is a white to off-white, crystalline powder which is slightly soluble in water but freely soluble in sodium hydroxide solution. ACCURETIC is available for oral use as fixed combination tablets in three strengths of quinapril with hydrochlorothiazide: 10 mg with 12.5 mg (ACCURETIC 10/12.5), 20 mg with 12.5 mg (ACCURETIC 20/12.5), and 20 mg with 25 mg (ACCURETIC 20/25). Inactive ingredients: candelilla wax, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. CLINICAL PHARMACOLOGY Mechanism of Action: The principal metabolite of quinapril, quinaprilat, is an inhibitor of ACE activity in human subjects and animals. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine, or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with quinapril alone resulted in mean increases in potassium of 0.07 mmol/L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in non-blacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldolsterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown. Pharmacokinetics and Metabolism: The rate and extent of absorption of quinapril and hydrochlorothiazide from ACCURETIC tablets are not different, respectively, from the rate and extent of absorption of quinapril and hydrochlorothiazide from immediate- release monotherapy formulations, either administered concurrently or separately. Following oral administration of Accupril (quinapril monotherapy) tablets, peak plasma quinapril concentrations are observed within 1 hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and more complete (50% to 80%). The rate of quinapril absorption was reduced by 14% when ACCURETIC tablets were administered with a high-fat meal as compared to fasting, while the extent of absorption was not affected. The rate of hydrochlorothiazide absorption was reduced by 12% when ACCURETIC tablets were administered with a high-fat meal, while the extent of absorption was not significantly affected. Therefore, ACCURETIC may be administered without regard to food. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of quinapril, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours postdose. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6 to 7.8 L/kg, consistent with measured plasma protein binding of 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6 to 1.8 times those measured in plasma. Some placental passage occurred when quinapril was administered to pregnant rats. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. Hydrochlorothiazide crosses the placenta freely but not the blood-brain barrier. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat is reduced in elderly patients (≥65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5- to 80-mg doses and 40- to 160-mg in multiple daily doses. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacodynamics and Clinical Effects: Single doses of 20 mg of quinapril provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20-mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 to 80 mg. Administration of 10 to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted (see WARNINGS). Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks. In multiple-dose studies, 10 to 80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5 to 11/3 to 7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice-daily dosing tended to give a somewhat lower trough blood pressure than once-daily dosing with the same total dose. The antihypertensive effect of quinapril continues during long-term therapy, with no evidence of loss of effectiveness. Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. Therapeutic effects of quinapril appear to be the same for elderly (≥65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. In patients with hypertension, quinapril 10 to 40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Use of quinapril with a thiazide diuretic gives blood pressure lowering effect greater than that seen with either agent alone. In clinical trials of quinapril/hydrochlorothiazide using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects were sustained for at least 24 hours, and increased with increasing dose of either component. Although quinapril monotherapy is somewhat less effective in blacks than in non-blacks, the efficacy of combination therapy appears to be independent of race. By blocking the renin- angiotensin-aldosterone axis, administration of quinapril tends to reduce the potassium loss associated with the diuretic. In clinical trials of ACCURETIC, the average change in serum potassium was near zero when 2.5 to 40 mg of quinapril was combined with hydrochlorothiazide 6.25 mg, and the average subject who received 10 to 20/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. INDICATIONS AND USAGE ACCURETIC is indicated for the treatment of hypertension. This fixed combination is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION). In using ACCURETIC, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that quinapril does not have a similar risk (see WARNINGS: Neutropenia/Agranulocytosis). Angioedema in Black Patients: Black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks. It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS ACCURETIC is contraindicated in patients who are hypersensitive to quinapril or hydrochlorothiazide and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. Because of the hydrochlorothiazide components, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. WARNINGS Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin converting inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including quinapril) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving quinapril. In two similarly sized US postmarketing quinapril trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in Study 1 and 2, respectively) and 0.39% and 0.17% of non-blacks. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with ACCURETIC should be discontinued immediately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE REACTIONS). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients With a History of Angioedema: Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also CONTRAINDICATIONS). Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with Hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent challenge. Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Hypotension: ACCURETIC can cause symptomatic hypotension, probably not more frequently than either monotherapy. It was reported in 1.2% of 1,571 patients receiving ACCURETIC during clinical trials. Like other ACE inhibitors, quinapril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension sometimes associated with oliguria and/or progressive azotemia, and rarely acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis or severe volume and/or salt depletion of any etiology. Volume and/or salt depletion should be corrected before initiating therapy with ACCURETIC. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ACCURETIC should be used cautiously in patients receiving concomitant therapy with other antihypertensives. The thiazide component of ACCURETIC may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic- blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patients. In patients at risk of excessive hypotension, therapy with ACCURETIC should be started under close medical supervision. Such patients should be followed closely for the first 2 weeks of treatment and whenever the dosage of quinapril or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. If excessive hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of normal saline. ACCURETIC treatment usually can be continued following restoration of blood pressure and volume. If symptomatic hypotension develops, a dose reduction or discontinuation of ACCURETIC may be necessary. Impaired Renal Function: ACCURETIC should be used with caution in patients with severe renal disease. Thiazides may precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative. When the renin-angiotensin-aldosterone system is inhibited by quinapril, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin aldosterone system, treatment with angiotensin-converting enzyme inhibitors (including quinapril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral renal artery stenosis, treatment with ACE inhibitors was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of ACE inhibitor, concomitant diuretic, or both. When such patients are treated with ACCURETIC, renal function should be monitored during the first few weeks of therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some quinapril-treated hypertensive patients with no apparent preexisting renal vascular diseases have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ACCURETIC may be required. Evaluation of the hypertensive patients should also include assessment of the renal function (see DOSAGE AND ADMINISTRATION). Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. Available data from clinical trials of quinapril are insufficient to show that, in patients without prior reactions to other ACE inhibitors, quinapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACCURETIC should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of quinapril as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, quinapril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or peritoneal dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Removal of quinapril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means. Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that occurred in adults. No teratogenic effects of quinapril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. No teratogenic effects of ACCURETIC were seen in studies of pregnant rats and rabbits. On a mg/kg (quinapril/hydrochlorothiazide) basis, the doses used were up to 188/94 times (in rats) and 0.6/0.3 times (in rabbits) the maximum recommended human dose. Impaired Hepatic Function: ACCURETIC should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterases, patients with impaired liver function could develop markedly elevated plasma levels of quinapril. No normal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. PRECAUTIONS General Derangements of Serum Electrolytes: In clinical trials, hyperkalemia (serum potassium ≥5.8 mmol/L) occurred in approximately 2% of patients receiving quinapril. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Treatment with thiazide diuretics has been associated with hypokalemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting. Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH. The opposite effects of quinapril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients, so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Chloride deficits secondary to thiazide therapy are generally mild and require specific treatment only under extraordinary circumstances (eg, in liver disease or renal disease). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been observed, with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration) have not been seen. Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result. Other Metabolic Disturbances: Thiazide diuretics tend to reduce glucose tolerance and to raise serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but frank gout or overt diabetes may be precipitated in susceptible patients. Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, quinapril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Information for Patients Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients receiving ACCURETIC should be told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until after consulting with the prescribing physician. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. Symptomatic Hypotension: A patient receiving ACCURETIC should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patient should be told that if syncope occurs, ACCURETIC should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the same consequences of lightheadedness and possible syncope. Patients planning to undergo major surgery and/ or general or spinal anesthesia should be told to inform their physicians that they are taking an ACE inhibitor. Hyperkalemia: A patient receiving ACCURETIC should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Neutropenia: Patients should be told to promptly report any indication of infection (eg, sore throat, fever) which could be a sign of neutropenia. NOTE: As with many other drugs, certain advice to patients being treated with quinapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Laboratory Tests The hydrochlorothiazide component of ACCURETIC may decrease serum PBI levels without signs of thyroid disturbance. Therapy with ACCURETIC should be interrupted for a few days before carrying out tests of parathyroid function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Potassium Supplements and Potassium-Sparing Diuretics: As noted above (“Derangements of Serum Electrolytes”), the net effect of ACCURETIC may be to elevate a patient’s serum potassium, to reduce it, or to leave it unchanged. Potassium- sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with ACCURETIC, a thiazide diuretic is coadministered with the ACE inhibitor. ACCURETIC and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. Tetracycline and Other Drugs That Interact with Magnesium: Simultaneous administration of tetracycline with quinapril reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in quinapril tablets. This interaction should be considered if coprescribing quinapril and tetracycline or other drugs that interact with magnesium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Other Agents: Drug interaction studies of quinapril and other agents showed: • Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of quinapril. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice daily. • Quinapril treatment did not affect the pharmacokinetics of digoxin. • No pharmacokinetic interaction was observed when single doses of quinapril and hydrochlorothiazide were administered concomitantly. When administered concurrently, the following drugs may interact with thiazide diuretics. • Alcohol, Barbiturates, or Narcotics—potentiation of orthostatic hypotension may occur. • Antidiabetic Drugs (oral hypoglycemic agents and insulin)—dosage adjustments of the antidiabetic drug may be required. • Cholestyramine and Colestipol Resin—absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. • Corticosteroids, ACTH—intensified electrolyte depletion, particularly hypokalemia. • Pressor Amines (eg, norepinephrine)—possible decreased response to pressor amines, but not sufficient to preclude their therapeutic use. • Skeletal Muscle Relaxants, Nondepolarizing (eg, tubocurarine)—possible increased responsiveness to the muscle relaxant. • Nonsteroidal Antiinflammatory Drugs—the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal antiinflammatory agents. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted in animals with ACCURETIC. Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 or 60 times the maximum human daily dose, respectively, on a mg/kg basis and 3.8 or 10 times the maximum human daily dose on a mg/m2 basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively). Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was “equivocal” evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese hamster ovary (CHO) test for chromosomal aberrations; or in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) test and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1300 µg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diets, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS: Fetal/Neonatal Morbidity and Mortality. Nursing Mothers Because quinapril and hydrochlorothiazide are secreted in human milk, caution should be exercised when ACCURETIC is administered to a nursing woman. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of quinapril in infants, a decision should be made whether to discontinue nursing or to discontinue ACCURETIC, taking into account the importance of the drug to the mother. Geriatric Use Clinical studies of quinapril HCl/hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Pediatric Use Safety and effectiveness of ACCURETIC in children have not been established. ADVERSE REACTIONS ACCURETIC has been evaluated for safety in 1571 patients in controlled and uncontrolled studies. Of these, 498 were given quinapril plus hydrochlorothiazide for at This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda least 1 year, with 153 patients extending combination therapy for over 2 years. In clinical trials with ACCURETIC, no adverse experience specific to the combination has been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with quinapril or hydrochlorothiazide. Adverse experiences were usually mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy because of adverse effects was required in 2.1% in patients in controlled studies. The most common reasons for discontinuation of therapy with ACCURETIC were cough (1.0%; see PRECAUTIONS) and headache (0.7%). Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 943 patients treated with quinapril plus hydrochlorothiazide in controlled trials are shown below. Percent of Patients in Controlled Trials Quinapril/HCTZ Placebo N = 943 N = 100 Headache 6.7 30.0 Dizziness 4.8 4.0 Coughing 3.2 2.0 Fatigue 2.9 3.0 Myalgia 2.4 5.0 Viral Infection 1.9 4.0 Rhinitis 2.0 3.0 Nausea and/or Vomiting 1.8 6.0 Abdominal Pain 1.7 4.0 Back Pain 1.5 2.0 Diarrhea 1.4 1.0 Upper Respiratory Infection 1.3 4.0 Insomnia 1.2 2.0 Somnolence 1.2 0.0 Bronchitis 1.2 1.0 Dyspepsia 1.2 2.0 Asthenia 1.1 1.0 Pharyngitis 1.1 2.0 Vasodilatation 1.0 1.0 Vertigo 1.0 2.0 Chest Pain 1.0 2.0 Clinical adverse experiences probably, possibly, or definitely related or of uncertain relationship to therapy occurring in ≥0.5% to <1.0% (except as noted) of the patients treated with quinapril/HCTZ in controlled and uncontrolled trials (N=1571) and less This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda frequent, clinically significant events seen in clinical trials or postmarketing experience (the rarer events are in italics) include (listed by body system): This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BODY AS A WHOLE: Asthenia, Malaise CARDIOVASCULAR: Palpitation, Tachycardia, Heart Failure, Hyperkalemia, Myocardial Infarction, Cerebrovascular Accident, Hypertensive Crisis, Angina Pectoris, Orthostatic Hypotension, Cardiac Rhythm Disturbance GASTROINTESTINAL: Mouth or Throat Dry, Gastrointestinal Hemorrhage, Pancreatitis, Abnormal Liver Function Tests NERVOUS/PSYCHIATRIC: Nervousness, Vertigo, Paresthesia RESPIRATORY: Sinusitis, Dyspnea INTEGUMENTARY: Pruritus, Sweating Increased, Erythema Multiforme, Exfoliative Dermatitis, Photosensitivity Reaction, Alopecia, Pemphigus UROGENITAL SYSTEM: Acute Renal Failure, Impotence OTHER: Agranulocytosis, Thrombocytopenia, Arthralgia Angioedema: Angioedema has been reported in 0.1% of patients receiving quinapril (0.1%) (see WARNINGS). Fetal/Neonatal Morbidity and See WARNINGS: Fetal/Neonatal Morbidity and Mortality: Mortality Postmarketing Experience The following serious nonfatal adverse events, regardless of their relationship to quinapril and HCTZ combination tablets, have been reported during extensive postmarketing experience: BODY AS A WHOLE: Shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, hernia and anaphylactoid reaction. CARDIOVASCULAR SYSTEM: Bradycardia, cor pulmonale, vasculitis, and deep thrombosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIGESTIVE SYSTEM: Gastrointestinal carcinoma, cholestatic jaundice, hepatitis, esophagitis, vomiting, and diarrhea. HEMIC SYSTEM: Anemia. METABOLIC AND NUTRITIONAL DISORDERS: Weight loss. MUSCULOSKELETAL SYSTEM: Myopathy, myositis, and arthritis. NERVOUS SYSTEM: Paralysis, hemiplegia, speech disorder, abnormal gait, meningism, and amnesia. RESPIRATORY SYSTEM: Pneumonia, asthma, respiratory infiltration, and lung disorder. SKIN AND APPENDAGES: Urticaria, macropapular rash, and petechiases. SPECIAL SENSES: Abnormal vision. UROGENITAL SYSTEM: Kidney function abnormal, albuminuria, pyuria, hematuria, and nephrosis. Quinapril monotherapy has been evaluated for safety in 4960 patients. In clinical trials adverse events which occurred with quinapril were also seen with ACCURETIC. In addition, the following were reported for quinapril at an incidence >0.5%: depression, back pain, constipation, syncope, and amblyopia. Hydrochlorothiazide has been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BODY AS A WHOLE: Weakness. CARDIOVASCULAR: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics). DIGESTIVE: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia. NEUROLOGIC: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. MUSCULOSKELETAL: Muscle spasm. HEMATOLOGIC: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and hemolytic anemia. RENAL: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS). METABOLIC: Hyperglycemia, glycosuria, and hyperuricemia. HYPERSENSITIVITY: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Clinical Laboratory Test Findings Serum Electrolytes: See PRECAUTIONS. Creatinine, Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4%, respectively, of patients treated with ACCURETIC. Most increases were minor and reversible, which can occur in patients with essential hypertension but most frequently in patients with renal artery stenosis (see PRECAUTIONS). PBI and Tests of Parathyroid Function: See PRECAUTIONS. Hematology: See WARNINGS. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other (causal relationships unknown): Other clinically important changes in standard laboratory tests were rarely associated with ACCURETIC administration. Elevations in uric acid, glucose, magnesium, cholesterol, triglyceride, and calcium (see PRECAUTIONS) have been reported. OVERDOSAGE No specific information is available on the treatment of overdosage with ACCURETIC or quinapril monotherapy; treatment should be symptomatic and supportive. Therapy with ACCURETIC should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures. The oral median lethal dose of quinapril/hydrochlorothiazide in combination ranges from 1063/664 to 4640/2896 mg/kg in mice and rats. Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats. In single-dose studies of hydrochlorothiazide, most rats survived doses up to 2.75 g/kg. Data from human overdoses of ACE inhibitors are scanty; the most likely manifestation of human quinapril overdosage is hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose. No data are available to suggest physiological maneuvers (eg, maneuvers to change the pH of the urine) that might accelerate elimination of quinapril and its metabolites. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of quinapril is achieved through This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution. DOSAGE AND ADMINISTRATION As individual monotherapy, quinapril is an effective treatment of hypertension in once- daily doses of 10 to 80 mg and hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of quinapril/hydrochlorothiazide combination therapy using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing dose of either component. The side effects (see WARNINGS) of quinapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. Therapy with any combination of quinapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens that combine low doses of hydrochlorothiazide with quinapril produce minimal effects on serum potassium. In clinical trials of ACCURETIC, the average change in serum potassium was near zero in subjects who received HCTZ 6.25 mg in the combination, and the average subject who received 10 to 40/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Therapy Guided by Clinical Effect Patients whose blood pressures are not adequately controlled with quinapril monotherapy may instead be given ACCURETIC 10/12.5 or 20/12.5. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve blood pressure control with less electrolyte disturbance if they are switched to ACCURETIC 10/12.5 or 20/12.5. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Replacement Therapy For convenience, patients who are adequately treated with 20 mg of quinapril and 25 mg of hydrochlorothiazide and experience no significant electrolyte disturbances may instead wish to receive ACCURETIC 20/25. Use in Renal Impairment Regimens of therapy with ACCURETIC need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73 m2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides. Therefore, ACCURETIC is not recommended for use in these patients. HOW SUPPLIED ACCURETIC is available in tablets of three different strengths: 10/12.5 tablets: pink, scored elliptical, biconvex, film-coated tablets coded “PD 222” on one side. Each tablet contains 10 mg of quinapril and 12.5 mg of hydrochlorothiazide. N0071-0222-23: 90 tablet bottles 20/12.5 tablets: pink, scored triangular, film-coated tablets coded “PD 220” on one side. Each tablet contains 20 mg of quinapril and 12.5 mg of hydrochlorothiazide. N0071-0220-23: 90 tablet bottles 20/25 tablets: pink, round, biconvex, film-coated tablets coded “PD 223” on one side. Each tablet contains 20 mg of quinapril and 25 mg of hydrochlorothiazide. N0071-0223-23: 90 tablet bottles Dispense in tight containers as defined in the USP. Store at Controlled Room Temperature 20–25°C (68–77°F) [see USP]. Rx only Company logo This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LAB-0216-7.0 Revised April 2009 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:47.306456	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020125s007lbl.pdf', 'application_number': 20125, 'submission_type': 'SUPPL ', 'submission_number': 7}
12,235	ACCURETIC™ (quinapril HCl/hydrochlorothiazide) Tablets USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ACCURETIC should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality. DESCRIPTION ACCURETIC is a fixed-combination tablet that combines an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride, and a thiazide diuretic, hydrochlorothiazide. Quinapril hydrochloride is chemically described as [3S-[2[R(R)], 3R*]]-2-[2-[[1 (ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3 isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5. HCl and its structural formula is: structural formula Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. Reference ID: 2920621 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hydrochlorothiazide is chemically described as: 6-Chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8CIN3O4S2 and its structural formula is: structural formula Hydrochlorothiazide is a white to off-white, crystalline powder which is slightly soluble in water but freely soluble in sodium hydroxide solution. ACCURETIC is available for oral use as fixed combination tablets in three strengths of quinapril with hydrochlorothiazide: 10 mg with 12.5 mg (ACCURETIC 10/12.5), 20 mg with 12.5 mg (ACCURETIC 20/12.5), and 20 mg with 25 mg (ACCURETIC 20/25). Inactive ingredients: candelilla wax, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. CLINICAL PHARMACOLOGY Mechanism of Action: The principal metabolite of quinapril, quinaprilat, is an inhibitor of ACE activity in human subjects and animals. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine, or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with quinapril alone resulted in mean increases in potassium of 0.07 mmol/L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Reference ID: 2920621 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in non-blacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldolsterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown. Pharmacokinetics and Metabolism: The rate and extent of absorption of quinapril and hydrochlorothiazide from ACCURETIC tablets are not different, respectively, from the rate and extent of absorption of quinapril and hydrochlorothiazide from immediate- release monotherapy formulations, either administered concurrently or separately. Following oral administration of Accupril (quinapril monotherapy) tablets, peak plasma quinapril concentrations are observed within 1 hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and more complete (50% to 80%). The rate of quinapril absorption was reduced by 14% when ACCURETIC tablets were administered with a high-fat meal as compared to fasting, while the extent of absorption was not affected. The rate of hydrochlorothiazide absorption was reduced by 12% when ACCURETIC tablets were administered with a high-fat meal, while the extent of absorption was not significantly affected. Therefore, ACCURETIC may be administered without regard to food. Reference ID: 2920621 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of quinapril, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours postdose. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6 to 7.8 L/kg, consistent with measured plasma protein binding of 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6 to 1.8 times those measured in plasma. Some placental passage occurred when quinapril was administered to pregnant rats. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. Hydrochlorothiazide crosses the placenta freely but not the blood-brain barrier. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat is reduced in elderly patients (≥65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5- to 80-mg doses and 40- to 160-mg in multiple daily doses. Reference ID: 2920621 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacodynamics and Clinical Effects: Single doses of 20 mg of quinapril provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20-mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 to 80 mg. Administration of 10 to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted (see WARNINGS). Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks. In multiple-dose studies, 10 to 80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5 to 11/3 to 7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice-daily dosing tended to give a somewhat lower trough blood pressure than once-daily dosing with the same total dose. The antihypertensive effect of quinapril continues during long-term therapy, with no evidence of loss of effectiveness. Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. Therapeutic effects of quinapril appear to be the same for elderly (≥65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. In patients with hypertension, quinapril 10 to 40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. Reference ID: 2920621 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Use of quinapril with a thiazide diuretic gives blood pressure lowering effect greater than that seen with either agent alone. In clinical trials of quinapril/hydrochlorothiazide using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects were sustained for at least 24 hours, and increased with increasing dose of either component. Although quinapril monotherapy is somewhat less effective in blacks than in non-blacks, the efficacy of combination therapy appears to be independent of race. By blocking the renin- angiotensin-aldosterone axis, administration of quinapril tends to reduce the potassium loss associated with the diuretic. In clinical trials of ACCURETIC, the average change in serum potassium was near zero when 2.5 to 40 mg of quinapril was combined with hydrochlorothiazide 6.25 mg, and the average subject who received 10 to 20/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. INDICATIONS AND USAGE ACCURETIC is indicated for the treatment of hypertension. This fixed combination is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION). In using ACCURETIC, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that quinapril does not have a similar risk (see WARNINGS: Neutropenia/Agranulocytosis). Angioedema in Black Patients: Black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks. It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. Reference ID: 2920621 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS ACCURETIC is contraindicated in patients who are hypersensitive to quinapril or hydrochlorothiazide and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. Because of the hydrochlorothiazide components, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. WARNINGS Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin converting inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including quinapril) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving quinapril. In two similarly sized US postmarketing quinapril trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in Study 1 and 2, respectively) and 0.39% and 0.17% of non-blacks. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with ACCURETIC should be discontinued immediately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE REACTIONS). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal Reference ID: 2920621 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients With a History of Angioedema: Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also CONTRAINDICATIONS). Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with Hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent challenge. Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Hypotension: ACCURETIC can cause symptomatic hypotension, probably not more frequently than either monotherapy. It was reported in 1.2% of 1,571 patients receiving ACCURETIC during clinical trials. Like other ACE inhibitors, quinapril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension sometimes associated with oliguria and/or progressive azotemia, and rarely acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis or severe volume and/or salt depletion of any etiology. Volume and/or salt depletion should be corrected before initiating therapy with ACCURETIC. Reference ID: 2920621 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ACCURETIC should be used cautiously in patients receiving concomitant therapy with other antihypertensives. The thiazide component of ACCURETIC may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic- blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patients. In patients at risk of excessive hypotension, therapy with ACCURETIC should be started under close medical supervision. Such patients should be followed closely for the first 2 weeks of treatment and whenever the dosage of quinapril or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. If excessive hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of normal saline. ACCURETIC treatment usually can be continued following restoration of blood pressure and volume. If symptomatic hypotension develops, a dose reduction or discontinuation of ACCURETIC may be necessary. Impaired Renal Function: ACCURETIC should be used with caution in patients with severe renal disease. Thiazides may precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative. When the renin-angiotensin-aldosterone system is inhibited by quinapril, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin aldosterone system, treatment with angiotensin-converting enzyme inhibitors (including quinapril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral renal artery stenosis, treatment with ACE inhibitors was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of ACE inhibitor, concomitant diuretic, or both. When such patients are treated with ACCURETIC, renal function should be monitored during the first few weeks of therapy. Reference ID: 2920621 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some quinapril-treated hypertensive patients with no apparent preexisting renal vascular diseases have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ACCURETIC may be required. Evaluation of the hypertensive patients should also include assessment of the renal function (see DOSAGE AND ADMINISTRATION). Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. Available data from clinical trials of quinapril are insufficient to show that, in patients without prior reactions to other ACE inhibitors, quinapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACCURETIC should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Reference ID: 2920621 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of quinapril as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, quinapril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or peritoneal dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Removal of quinapril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means. Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that occurred in adults. No teratogenic effects of quinapril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. No teratogenic effects of ACCURETIC were seen in studies of pregnant rats and rabbits. On a mg/kg (quinapril/hydrochlorothiazide) basis, the doses used were up to 188/94 times (in rats) and 0.6/0.3 times (in rabbits) the maximum recommended human dose. Impaired Hepatic Function: ACCURETIC should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterases, patients with impaired liver function could develop markedly elevated plasma levels of quinapril. No normal Reference ID: 2920621 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. PRECAUTIONS General Derangements of Serum Electrolytes: In clinical trials, hyperkalemia (serum potassium ≥5.8 mmol/L) occurred in approximately 2% of patients receiving quinapril. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Treatment with thiazide diuretics has been associated with hypokalemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting. Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving Reference ID: 2920621 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH. The opposite effects of quinapril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients, so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Chloride deficits secondary to thiazide therapy are generally mild and require specific treatment only under extraordinary circumstances (eg, in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been observed, with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration) have not been seen. Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result. Other Metabolic Disturbances: Thiazide diuretics tend to reduce glucose tolerance and to raise serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but frank gout or overt diabetes may be precipitated in susceptible patients. Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, quinapril will block the angiotensin II formation that could Reference ID: 2920621 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Information for Patients Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients receiving ACCURETIC should be told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until after consulting with the prescribing physician. Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. Symptomatic Hypotension: A patient receiving ACCURETIC should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patient should be told that if syncope occurs, ACCURETIC should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the same consequences of lightheadedness and possible syncope. Patients planning to undergo major surgery and/ or general or spinal anesthesia should be told to inform their physicians that they are taking an ACE inhibitor. Hyperkalemia: A patient receiving ACCURETIC should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Neutropenia: Patients should be told to promptly report any indication of infection (eg, sore throat, fever) which could be a sign of neutropenia. Reference ID: 2920621 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOTE: As with many other drugs, certain advice to patients being treated with quinapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Laboratory Tests The hydrochlorothiazide component of ACCURETIC may decrease serum PBI levels without signs of thyroid disturbance. Therapy with ACCURETIC should be interrupted for a few days before carrying out tests of parathyroid function. Drug Interactions Potassium Supplements and Potassium-Sparing Diuretics: As noted above (“Derangements of Serum Electrolytes”), the net effect of ACCURETIC may be to elevate a patient’s serum potassium, to reduce it, or to leave it unchanged. Potassium- sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with ACCURETIC, a thiazide diuretic is coadministered with the ACE inhibitor. ACCURETIC and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. Tetracycline and Other Drugs That Interact with Magnesium: Simultaneous administration of tetracycline with quinapril reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in quinapril tablets. This interaction should be considered if coprescribing quinapril and tetracycline or other drugs that interact with magnesium. Reference ID: 2920621 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Other Agents: Drug interaction studies of quinapril and other agents showed: • Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of quinapril. • The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice daily. • Quinapril treatment did not affect the pharmacokinetics of digoxin. • No pharmacokinetic interaction was observed when single doses of quinapril and hydrochlorothiazide were administered concomitantly. When administered concurrently, the following drugs may interact with thiazide diuretics. • Alcohol, Barbiturates, or Narcotics—potentiation of orthostatic hypotension may occur. • Antidiabetic Drugs (oral hypoglycemic agents and insulin)—dosage adjustments of the antidiabetic drug may be required. • Cholestyramine and Colestipol Resin—absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. • Corticosteroids, ACTH—intensified electrolyte depletion, particularly hypokalemia. Reference ID: 2920621 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Pressor Amines (eg, norepinephrine)—possible decreased response to pressor amines, but not sufficient to preclude their therapeutic use. • Skeletal Muscle Relaxants, Nondepolarizing (eg, tubocurarine)—possible increased responsiveness to the muscle relaxant. • Nonsteroidal Antiinflammatory Drugs—the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal antiinflammatory agents. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted in animals with ACCURETIC. Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 or 60 times the maximum human daily dose, respectively, on a mg/kg basis and 3.8 or 10 times the maximum human daily dose on a mg/m2 basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively). Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was “equivocal” evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese hamster ovary (CHO) test for Reference ID: 2920621 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda chromosomal aberrations; or in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) test and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1300 µg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diets, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS: Fetal/Neonatal Morbidity and Mortality. Nursing Mothers Because quinapril and hydrochlorothiazide are secreted in human milk, caution should be exercised when ACCURETIC is administered to a nursing woman. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of quinapril in infants, a decision should be made whether to discontinue nursing or to discontinue ACCURETIC, taking into account the importance of the drug to the mother. Geriatric Use Clinical studies of quinapril HCl/hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Reference ID: 2920621 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness of ACCURETIC in children have not been established. ADVERSE REACTIONS ACCURETIC has been evaluated for safety in 1571 patients in controlled and uncontrolled studies. Of these, 498 were given quinapril plus hydrochlorothiazide for at least 1 year, with 153 patients extending combination therapy for over 2 years. In clinical trials with ACCURETIC, no adverse experience specific to the combination has been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with quinapril or hydrochlorothiazide. Adverse experiences were usually mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy because of adverse effects was required in 2.1% in patients in controlled studies. The most common reasons for discontinuation of therapy with ACCURETIC were cough (1.0%; see PRECAUTIONS) and headache (0.7%). Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 943 patients treated with quinapril plus hydrochlorothiazide in controlled trials are shown below. Reference ID: 2920621 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Percent of Patients in Controlled Trials Quinapril/HCTZ Placebo N = 943 N = 100 Headache 6.7 30.0 Dizziness 4.8 4.0 Coughing 3.2 2.0 Fatigue 2.9 3.0 Myalgia 2.4 5.0 Viral Infection 1.9 4.0 Rhinitis 2.0 3.0 Nausea and/or Vomiting 1.8 6.0 Abdominal Pain 1.7 4.0 Back Pain 1.5 2.0 Diarrhea 1.4 1.0 Upper Respiratory Infection 1.3 4.0 Insomnia 1.2 2.0 Somnolence 1.2 0.0 Bronchitis 1.2 1.0 Dyspepsia 1.2 2.0 Asthenia 1.1 1.0 Pharyngitis 1.1 2.0 Vasodilatation 1.0 1.0 Vertigo 1.0 2.0 Chest Pain 1.0 2.0 Clinical adverse experiences probably, possibly, or definitely related or of uncertain relationship to therapy occurring in ≥0.5% to <1.0% (except as noted) of the patients treated with quinapril/HCTZ in controlled and uncontrolled trials (N=1571) and less frequent, clinically significant events seen in clinical trials or postmarketing experience (the rarer events are in italics) include (listed by body system): Reference ID: 2920621 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BODY AS A WHOLE: Asthenia, Malaise CARDIOVASCULAR: Palpitation, Tachycardia, Heart Failure, Hyperkalemia, Myocardial Infarction, Cerebrovascular Accident, Hypertensive Crisis, Angina Pectoris, Orthostatic Hypotension, Cardiac Rhythm Disturbance GASTROINTESTINAL: Mouth or Throat Dry, Gastrointestinal Hemorrhage, Pancreatitis, Abnormal Liver Function Tests NERVOUS/PSYCHIATRIC: Nervousness, Vertigo, Paresthesia RESPIRATORY: Sinusitis, Dyspnea INTEGUMENTARY: Pruritus, Sweating Increased, Erythema Multiforme, Exfoliative Dermatitis, Photosensitivity Reaction, Alopecia, Pemphigus UROGENITAL SYSTEM: Acute Renal Failure, Impotence OTHER: Agranulocytosis, Thrombocytopenia, Arthralgia Angioedema: Angioedema has been reported in 0.1% of patients receiving quinapril (0.1%) (see WARNINGS). Fetal/Neonatal Morbidity and See WARNINGS: Fetal/Neonatal Morbidity and Mortality: Mortality Postmarketing Experience The following serious nonfatal adverse events, regardless of their relationship to quinapril and HCTZ combination tablets, have been reported during extensive postmarketing experience: BODY AS A WHOLE: Shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, hernia and anaphylactoid reaction. CARDIOVASCULAR SYSTEM: Bradycardia, cor pulmonale, vasculitis, and deep thrombosis. Reference ID: 2920621 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIGESTIVE SYSTEM: Gastrointestinal carcinoma, cholestatic jaundice, hepatitis, esophagitis, vomiting, and diarrhea. HEMIC SYSTEM: Anemia. METABOLIC AND NUTRITIONAL DISORDERS: Weight loss. MUSCULOSKELETAL SYSTEM: Myopathy, myositis, and arthritis. NERVOUS SYSTEM: Paralysis, hemiplegia, speech disorder, abnormal gait, meningism, and amnesia. RESPIRATORY SYSTEM: Pneumonia, asthma, respiratory infiltration, and lung disorder. SKIN AND APPENDAGES: Urticaria, macropapular rash, and petechiases. SPECIAL SENSES: Abnormal vision. UROGENITAL SYSTEM: Kidney function abnormal, albuminuria, pyuria, hematuria, and nephrosis. Quinapril monotherapy has been evaluated for safety in 4960 patients. In clinical trials adverse events which occurred with quinapril were also seen with ACCURETIC. In addition, the following were reported for quinapril at an incidence >0.5%: depression, back pain, constipation, syncope, and amblyopia. Hydrochlorothiazide has been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency. Reference ID: 2920621 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BODY AS A WHOLE: Weakness. CARDIOVASCULAR: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics). DIGESTIVE: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia. NEUROLOGIC: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. MUSCULOSKELETAL: Muscle spasm. HEMATOLOGIC: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and hemolytic anemia. RENAL: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS). METABOLIC: Hyperglycemia, glycosuria, and hyperuricemia. HYPERSENSITIVITY: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Clinical Laboratory Test Findings Serum Electrolytes: See PRECAUTIONS. Creatinine, Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4%, respectively, of patients treated with ACCURETIC. Most increases were minor and reversible, which can occur in patients with essential hypertension but most frequently in patients with renal artery stenosis (see PRECAUTIONS). PBI and Tests of Parathyroid Function: See PRECAUTIONS. Hematology: See WARNINGS. Reference ID: 2920621 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other (causal relationships unknown): Other clinically important changes in standard laboratory tests were rarely associated with ACCURETIC administration. Elevations in uric acid, glucose, magnesium, cholesterol, triglyceride, and calcium (see PRECAUTIONS) have been reported. OVERDOSAGE No specific information is available on the treatment of overdosage with ACCURETIC or quinapril monotherapy; treatment should be symptomatic and supportive. Therapy with ACCURETIC should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures. The oral median lethal dose of quinapril/hydrochlorothiazide in combination ranges from 1063/664 to 4640/2896 mg/kg in mice and rats. Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats. In single-dose studies of hydrochlorothiazide, most rats survived doses up to 2.75 g/kg. Data from human overdoses of ACE inhibitors are scanty; the most likely manifestation of human quinapril overdosage is hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose. No data are available to suggest physiological maneuvers (eg, maneuvers to change the pH of the urine) that might accelerate elimination of quinapril and its metabolites. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of quinapril is achieved through Reference ID: 2920621 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution. DOSAGE AND ADMINISTRATION As individual monotherapy, quinapril is an effective treatment of hypertension in once- daily doses of 10 to 80 mg and hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of quinapril/hydrochlorothiazide combination therapy using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing dose of either component. The side effects (see WARNINGS) of quinapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. Therapy with any combination of quinapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens that combine low doses of hydrochlorothiazide with quinapril produce minimal effects on serum potassium. In clinical trials of ACCURETIC, the average change in serum potassium was near zero in subjects who received HCTZ 6.25 mg in the combination, and the average subject who received 10 to 40/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Therapy Guided by Clinical Effect Patients whose blood pressures are not adequately controlled with quinapril monotherapy may instead be given ACCURETIC 10/12.5 or 20/12.5. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve blood pressure control with less electrolyte disturbance if they are switched to ACCURETIC 10/12.5 or 20/12.5. Reference ID: 2920621 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo Replacement Therapy For convenience, patients who are adequately treated with 20 mg of quinapril and 25 mg of hydrochlorothiazide and experience no significant electrolyte disturbances may instead wish to receive ACCURETIC 20/25. Use in Renal Impairment Regimens of therapy with ACCURETIC need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73 m2 (serum creatinine roughly ≤3 mg/dL or 265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides. Therefore, ACCURETIC is not recommended for use in these patients. HOW SUPPLIED ACCURETIC is available in tablets of three different strengths: 10/12.5 tablets: pink, scored elliptical, biconvex, film-coated tablets coded “PD 222” on one side. Each tablet contains 10 mg of quinapril and 12.5 mg of hydrochlorothiazide. N0071-0222-23: 90 tablet bottles 20/12.5 tablets: pink, scored triangular, film-coated tablets coded “PD 220” on one side. Each tablet contains 20 mg of quinapril and 12.5 mg of hydrochlorothiazide. N0071-0220-23: 90 tablet bottles 20/25 tablets: pink, round, biconvex, film-coated tablets coded “PD 223” on one side. Each tablet contains 20 mg of quinapril and 25 mg of hydrochlorothiazide. N0071-0223-23: 90 tablet bottles Dispense in tight containers as defined in the USP. Store at Controlled Room Temperature 20–25°C (68–77°F) [see USP]. Rx only Reference ID: 2920621 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LAB-0216-8.0 Revised February 2011 Reference ID: 2920621 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:47.452661	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020125s010lbl.pdf', 'application_number': 20125, 'submission_type': 'SUPPL ', 'submission_number': 10}
12,233	_______________________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlig hts do not include all the information needed to use OMNISCAN safely and effectively. See full prescribing information for OMNISCAN. OMNISCANTM (gadodiamide) Injection for Intravenous Use Initial U.S. Approval: 1993 WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) See full prescribing information for complete boxed warning. NOT FOR INTRATHECAL USE: • Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits (5.1). NSF: Gadolinium-based contrast agents (GBCAs) increase the risk for NSF amo ng patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic infor mation is essential and not av ailable with non-contrasted MRI or other modalities. • Do not administer OMNISCAN to patients with: ○ chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or ○ acute kidne y injur y (4). • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g., age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.2). ---------------------------RECENT MAJOR CHANGES--------------------------- Contraindications (4) 08/2013 Warnings and Precautions, Hypersensitivity Reactions (5.3) 08/2013 ----------------------------INDICATIONS AND USAGE-------------------------- OMNISCAN is a gadolinium-based contrast agent for diagnostic magnetic resonance imaging (MRI) indicated for intravenous use to: • Visualize lesions with abnormal vascularity in the brain, spine, and associated tissues (1.1) • Facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space (1.2) -----------------------DOSAGE AND ADMINISTRATION---------------------- • CNS – Adults and Pediatrics; 2-16 years of age: 0.2 mL/kg (0.1 mmol/kg) (2.1, 2.4) • Body – Adults and Pediatrics; 2-16 years of age: Kidney: 0.1 mL/kg (0.05 mmol/kg) Intrathoracic, intra-abdominal, and pelvic cavities: 0.2 mL/kg (0.1 mmol/kg) (2.2, 2.4) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Sterile aqueous solution for intravenous injection; 287 mg/mL (3) -------------------------------CONTRAINDICATIONS----------------------------- Patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), acute kidney injury, or prior hypersensitivity reaction to OMNISCAN (4). -----------------------WARNINGS AND PRECAUTIONS----------------------- • Nephrogenic Systemic Fibrosis (NSF) has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appears to increase the risk (5.2). • Anaphylactoid and other serious hypersensitivity reactions including fatal reactions have occurred particularly in patients with history of allergy or drug reactions. Monitor patients closely for need of emergency cardiorespiratory support (5.3). • Acute renal failure has occurred in patients with preexisting renal insufficiency. Use the lowest necessary dose of OMNISCAN and evaluate renal function in these patients (5.4). ------------------------------ADVERSE REACTIONS------------------------------ • The most frequent adverse reactions (≤ 3%) observed during OMNISCAN adult clinical studies were nausea, headache, and dizziness (6.1) • Serious or life-threatening reactions include: cardiac failure, arrhythmia and myocardial infarction (6.1, 6.3) To report SUSPECTED ADVERSE REACTIONS, contact GE Healthc are at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 08/2013 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) 1 INDICATIONS AND USAGE 1.1 CNS (Central Nervous System) 1.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 2 DOSAGE AND ADMINISTRATION 2.1 CNS (Central Nervous System) 2.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 2.3 Dosage Chart 2.4 Dosing Guidelines 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Not for Intrathecal Use 5.2 Nephrogenic Systemic Fibrosis 5.3 Hypersensitivity Reactions 5.4 Acute Renal Failure 5.5 Impaired Visualization of Lesions Detectable with Non-contrast MRI 5.6 Laboratory Test Findings 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience (Adults) 6.2 Clinical Studies Experience (Pediatrics) 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal/Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 CNS (Central Nervous System) 14.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) NOT FOR INTRATHECAL USE: Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits [see Warnings and Precautions (5.1)]. NSF: • Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. • Do not administer OMNISCAN to patients with: ○ chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or ○ acute kidney injury [see Contraindications (4)]. • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g., age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. • Do not exceed the recommended OMNISCAN dose and allow a sufficient period of time for elimination of the drug from the body prior to any readministration [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 CNS (Central Nervous System) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues [see Clinical Studies (14.1)]. 1.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 CNS (Central Nervous System) Adults: The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. Pediatric Patients (2-16 years): The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection [see Dosage and Administration (2.3)]. 2.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) Adult and Pediatric Patients (2-16 years of age): For imaging the kidney, the recommended dose of OMNISCAN is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) [see Dosage and Administration (2.3)]. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.3 Dosage Chart BODY WEIGHT kg lb PEDIATRIC 0.05 0.1 (mmol/kg) ADULTS 0.05 0.1 (mmol/kg) VOLUME (mL) VOLUME (mL) 12 26 1.2 2.4 - - 14 31 1.4 2.8 - - 16 35 1.6 3.2 - - 18 40 1.8 3.6 - - 20 44 2 4 - - 22 48 2.2 4.4 - - 24 53 2.4 4.8 - - 26 57 2.6 5.2 - - 28 62 2.8 5.6 - - 30 66 3 6 - - 40 88 4 8 4 8 50 110 5 10 5 10 60 132 6 12 6 12 70 154 7 14 7 14 80 176 8 16 8 16 90 198 - - 9 18 100 220 - - 10 20 110 242 - - 11 22 120 264 - - 12 24 130 286 - - 13 26 The heaviest patient in clinical studies weighed 136 kg. 2.4 Dosing Guidelines Inspect OMNISCAN visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not use the solution if it is discolored or particulate matter is present. Draw OMNISCAN into the syringe and use immediately. Discard any unused portion of OMNISCAN Injection. To ensure complete delivery of the desired volume of contrast medium, follow the injection of OMNISCAN with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of OMNISCAN. 3 DOSAGE FORMS AND STRENGTHS Sterile aqueous solution for intravenous injection; 287 mg/mL. 4 CONTRAINDICATIONS OMNISCAN is contraindicated in patients with: • chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or • acute kidney injury • prior hypersensitivity reaction to OMNISCAN 5 WARNINGS AND PRECAUTIONS 5.1 Not for Intrathecal Use Inadvertent intrathecal use of OMNISCAN has occurred and caused convulsions, coma, sensory and motor neurologic deficits. 5.2 Nephrogenic Systemic Fibrosis Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. Do not administer OMNISCAN to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following OMNISCAN administration to GE Healthcare (1-800-654 0118) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. When administering OMNISCAN, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to any readministration [see Boxed Warning, Contraindications (4), Clinical Pharmacology (12.2) and Dosage and Administration (2)]. 5.3 Hypersensitivity Reactions Anaphylactoid and anaphylactic reactions, with cardiovascular, respiratory and/or cutaneous manifestations, resulting in death have occurred. Personnel trained in resuscitation techniques and resuscitation equipment should be present prior to OMNISCAN administration. If a hypersensitivity reaction occurs, stop OMNISCAN Injection and immediately begin appropriate therapy. Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after OMNISCAN Injection. 5.4 Acute Renal Failure In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of OMNISCAN Injection. The risk of renal failure may increase with increasing dose of gadolinium contrast. Use the lowest necessary dose of contrast and evaluate renal function in patients with renal insufficiency. Acute renal failure was observed in < 1% of patients in OMNISCAN clinical studies [see Adverse Reactions (6)]. OMNISCAN is cleared by glomerular filtration. Hemodialysis also enhances OMNISCAN clearance [see Use in Specific Populations (8.5, 8.6)]. 5.5 Impaired Visualization of Lesions Detectable with Non-contrast MRI Paramagnetic contrast agents such as OMNISCAN might impair the visualization of lesions which are seen on the non-contrast MRI. This may be due to effects of the paramagnetic contrast agent, or imaging parameters. Exercise caution when OMNISCAN MRI scans are interpreted in the absence of a companion non-contrast MRI. 5.6 Laboratory Test Findings Asymptomatic, transitory changes in serum iron have been observed. The clinical significance is unknown. OMNISCAN interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals, resulting in serum calcium concentrations lower than the true values. In patients with normal renal function, this effect lasts for 12-24 hours. In patients with decreased renal function, the interference with calcium measurements is expected to last during the prolonged elimination of OMNISCAN. After patients receive OMNISCAN, careful attention should be used in selecting the type of method used to measure calcium. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Nephrogenic systemic fibrosis [see Warnings and Precautions (5.2)] • Hypersensitivity reactions [see Warnings and Precautions (5.3)] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Clinical Studies Experience (Adults) In clinical studies 1160 patients were exposed to OMNISCAN. The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. The majority of these reactions were of mild to moderate intensity. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following adverse reactions occurred in 1% or less of patients: Application Site Disorders: Injection site reaction. Autonomic Nervous System Disorders: Vasodilation. Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope. Cardiovascular Disorders: Cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis. Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, paresthesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine. Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena. Hearing and Vestibular Disorders: Tinnitus. Liver and Biliary System Disorders: Abnormal hepatic function. Musculoskeletal System Disorders: Arthralgia, myalgia. Respiratory System Disorders: Rhinitis, dyspnea. Skin and Appendage Disorders: Pruritus, rash, erythematous rash, sweating increased, urticaria. Special Senses, Other Disorders: Taste loss, taste perversion. Urinary System Disorders: Acute reversible renal failure. Vision Disorders: Abnormal vision. 6.2 Clinical Studies Experience (Pediatrics) In the 97 pediatric patients in CNS studies with OMNISCAN [see Clinical Studies (14.1)] and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults. 6.3 Postmarketing Experience Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during the postmarketing use of OMNISCAN: Nervous System Disorders: Inadvertent intrathecal use causes seizures, coma, paresthesia, paresis. General Disorders: Nephrogenic Systemic Fibrosis (NSF) [see Warnings and Precautions (5.2)]. Renal and Urinary System Disorders: In patients with pre-existing renal insufficiency: acute renal failure, renal impairment, blood creatinine increased [see Warnings and Precautions (5.4)]. 7 DRUG INTERACTIONS Specific drug interaction studies have not been conducted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: OMNISCAN has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to OMNISCAN administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. Adequate and well controlled studies in pregnant women have not been conducted. OMNISCAN should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering OMNISCAN to a nursing woman. 8.4 Pediatric Use The safety and efficacy of OMNISCAN at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of OMNISCAN in adults, a pediatric CNS imaging study, and safety data in the scientific literature. However, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pharmacokinetics of OMNISCAN have not been studied in pediatrics. The glomerular filtration rate of neonates and infants is much lower than that of adults. The pharmacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established. 8.5 Geriatric Use In clinical studies of OMNISCAN, 243 patients were between 65 and 80 years of age while 15 were over 80. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. OMNISCAN is excreted by the kidney, and the risk of toxic reactions to OMNISCAN is greater in patients with impaired renal function [see Warnings and Precautions (5.2, 5.4)]. Because elderly patients are more likely to have decreased renal function, select dose carefully and assess eGFR by laboratory testing before OMNISCAN use. 8.6 Renal/Hepatic Impairment Dose adjustments in renal or hepatic impairment have not been studied. Caution should be exercised in patients with impaired renal insufficiency [see Warnings and Precautions (5.2, 5.4)]. 10 OVERDOSAGE Clinical consequences of overdose with OMNISCAN have not been reported. The minimum lethal dose of intravenously administered OMNISCAN in rats and mice is greater than 20 mmol/kg (200 times the recommended human dose of 0.1 mmol/kg; 67 times the cumulative 0.3 mmol/kg dose). OMNISCAN is dialyzable. 11 DESCRIPTION OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection. OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl) 11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9•xH2O, and the following structural formula: Pertinent physicochemical data for OMNISCAN are noted below: PARAMETER Osmolality (mOsmol/kg water) @ 37°C 789 Viscosity (cP) @ 20°C 2 @ 37°C 1.4 Density (g/mL) @ 25°C 1.14 Specific gravity @ 25°C 1.15 OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics In magnetic resonance imaging, visualization of normal and pathologic tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2). OMNISCAN is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent. By increasing the relaxation rate, OMNISCAN decreases both the T1 and T2 relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity. OMNISCAN does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e.g., cysts, mature postoperative scars). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of OMNISCAN in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of OMNISCAN in various lesions are not known. There is no detectable biotransformation or decomposition of gadodiamide. 12.3 Pharmacokinetics The pharmacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean ± SD) of 3.7 ± 2.7 minutes and 77.8 ± 16 minutes, respectively. Gadodiamide is eliminated primarily in the urine with 95.4 ± 5.5% (mean ± SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200 ± 61 mL/kg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro. Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term animal studies have not been performed to evaluate the carcinogenic potential of gadodiamide. The results of the following genotoxicity assays were negative: in vitro bacterial reverse mutation assay, in vitro Chinese Hamster Ovary (CHO)/Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT) forward mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay at intravenous doses of 27 mmol/kg (approximately 7 times the maximum human dose based on a body surface area comparison). Impairment of male or female fertility was not observed in rats after intravenous administration three times per week at the maximum dose tested of 1.0 mmol/kg (approximately 0.5 times the maximum human dose based on a body surface area comparison). 14 CLINICAL STUDIES 14.1 CNS (Central Nervous System) OMNISCAN (0.1 mmol/kg) contrast enhancement in CNS MRI was evident in a study of 439 adults. In a study of sequential dosing, 57 adults received OMNISCAN 0.1 mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmol/kg). The MRIs were compared blindly. In 54/56 (96%) patients, OMNISCAN contrast enhancement was evident with both the 0.1 mmol/kg and cumulative 0.3 mmol/kg OMNISCAN doses relative to non-contrast MRI. In comparison to the non-contrast MRI, increased numbers of brain and spine lesions were noted in 42% of patients who received OMNISCAN at any dose. In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) OMNISCAN 0.1 mmol/kg dose provided more diagnostic value and in 30/56 (54%) the cumulative OMNISCAN 0.3 mmol/kg dose provided more diagnostic value. The usefulness of a single 0.3 mmol/kg bolus in comparison to the cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) has not been established. OMNISCAN as a single 0.1 mmol/kg dose was evaluated in 97 pediatric patients with a mean age of 8.9 (2-18) years referred for CNS MRI. Postcontrast MRI provided added diagnostic information, diagnostic confidence, and new patient management information in 76%, 67%, and 52%, respectively, of pediatrics. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN was evaluated in a controlled trial of 276 patients referred for body MRI. These patients had a mean age of 57 (9-88) years. Patients received 0.1 mmol/kg OMNISCAN for imaging the thorax (noncardiac), abdomen, and pelvic organs, or a dose of 0.05 mmol/kg for imaging the kidney. Pre- and post-OMNISCAN images were evaluated blindly for the degree of diagnostic value rated on a scale of “remarkably improved, improved, no change, worse, and cannot be determined.” The postcontrast results showed “remarkably improved” or “improved” diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients. In a dose ranging study 258 patients referred for body MRI received OMNISCAN 0.025, 0.05, 0.1 mmol/kg. The lowest effective dose of OMNISCAN for the kidney was 0.05 mmol/kg. 16 HOW SUPPLIED/STORAGE AND HANDLING OMNISCAN (gadodiamide) Injection is a sterile, clear, colorless to slightly yellow, aqueous solution containing 287 mg/mL of gadodiamide in rubber stoppered vials and prefilled syringes. OMNSICAN is supplied in the following sizes: 5 mL fill in 10 mL vial, box of 10 (NDC 0407-0690-05) 10 mL vial, box of 10 (NDC 0407-0690-10) 15 mL fill in 20 mL vial, box of 10 (NDC 0407-0690-15) 20 mL vial, box of 10 (NDC 0407-0690-20) 10 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-12) 15 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-17) 20 mL prefilled syringe, box of 10 (NDC 0407-0690-22) Prefill Plus™ needle-free system OMNISCAN 15 mL, box of 10 (NDC 0407-0691-62) Contains: OMNISCAN 15 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe Prefill Plus™ needle-free system OMNISCAN 20 mL, box of 10 (NDC 0407-0691-63) Contains: OMNISCAN 20 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe Protect OMNISCAN from strong daylight and direct exposure to sunlight. Do not freeze. Freezing can cause small cracks in the vials, which would compromise the sterility of the product. Do not use if the product is inadvertently frozen. Store OMNISCAN at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP]. 17 PATIENT COUNSELING INFORMATION Patients receiving OMNISCAN should be instructed to inform their physician if they: • are pregnant or breast feeding, or • have a history of renal and/or liver disease, convulsions, asthma or allergic respiratory disorders, or recent administration of gadolinium-based contrast. GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF: • Describe the clinical manifestations of NSF • Describe procedures to screen for the detection of renal impairment Instruct the patients to contact their physician if they develop signs or symptoms of NSF following OMNISCAN administration such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; or muscle weakness. Distributed by GE Healthcare Inc., Princeton, NJ Manufactured by GE Healthcare AS, Oslo, Norway OMNISCAN is a trademark of GE Healthcare. GE and the GE Monogram are trademarks of General Electric Company. © 2013 General Electric Company - All rights reserved. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda _______________________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlig hts do not include all the information needed to use OMNISCAN safely and effectively. See full prescribing information for OMNISCAN. OMNISCANTM (gadodiamide) Injection for Intravenous Use Pharmacy Bulk Pac kage Initial U.S. Approval: 1993 WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) See full prescribing information for complete boxed warning. NOT FOR INTRATHECAL USE: • Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits (5.1). NSF: Gadolinium-based contrast agents (GBCAs) increase the risk for NSF amo ng patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic infor mation is essential and not av ailable with non-contrasted MRI or other modalities. • Do not administer OMNISCAN to patients with: ○ chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or ○ acute kidne y injur y (4). • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g., age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.2). ---------------------------RECENT MAJOR CHANGES--------------------------- Contraindications (4) 08/2013 Warnings and Precautions, Hypersensitivity Reactions (5.3) 08/2013 ----------------------------INDICATIONS AND USAGE-------------------------- OMNISCAN is a gadolinium-based contrast agent for diagnostic magnetic resonance imaging (MRI) indicated for intravenous use to: • Visualize lesions with abnormal vascularity in the brain, spine, and associated tissues (1.1) • Facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space (1.2) -----------------------DOSAGE AND ADMINISTRATION---------------------- • Pharmacy Bulk Package – Not for Direct Infusion (11) • CNS – Adults and Pediatrics; 2-16 years of age: 0.2 mL/kg (0.1 mmol/kg) (2.1, 2.4) • Body – Adults and Pediatrics; 2-16 years of age: Kidney: 0.1 mL/kg (0.05 mmol/kg) Intrathoracic, intra-abdominal, and pelvic cavities: 0.2 mL/kg (0.1 mmol/kg) (2.2, 2.4) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Sterile aqueous solution for intravenous injection; 287 mg/mL (3) -------------------------------CONTRAINDICATIONS----------------------------- Patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), acute kidney injury, or prior hypersensitivity reaction to OMNISCAN (4). -----------------------WARNINGS AND PRECAUTIONS----------------------- • Nephrogenic Systemic Fibrosis (NSF) has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appears to increase the risk (5.2). • Anaphylactoid and other serious hypersensitivity reactions including fatal reactions have occurred particularly in patients with history of allergy or drug reactions. Monitor patients closely for need of emergency cardiorespiratory support (5.3). • Acute renal failure has occurred in patients with preexisting renal insufficiency. Use the lowest necessary dose of OMNISCAN and evaluate renal function in these patients (5.4). ------------------------------ADVERSE REACTIONS------------------------------ • The most frequent adverse reactions (≤ 3%) observed during OMNISCAN adult clinical studies were nausea, headache, and dizziness (6.1) • Serious or life-threatening reactions include: cardiac failure, arrhythmia and myocardial infarction (6.1, 6.3) To report SUSPECTED ADVERSE REACTIONS, contact GE Healthc are at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/me dwatc h. See 17 for PATIENT COUNSELING INFORMATION. Revised: 08/2013 FULL PRESCRIBING INFORMATION: CONTENTS WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) 1 INDICATIONS AND USAGE 1.1 CNS (Central Nervous System) 1.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 2 DOSAGE AND ADMINISTRATION 2.1 CNS (Central Nervous System) 2.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 2.3 Dosage Chart 2.4 Dosing Guidelines 2.5 Directions for Proper Use of OMNISCAN Pharmacy Bulk Package 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Not for Intrathecal Use 5.2 Nephrogenic Systemic Fibrosis 5.3 Hypersensitivity Reactions 5.4 Acute Renal Failure 5.5 Impaired Visualization of Lesions Detectable with Non-contrast MRI 5.6 Laboratory Test Findings 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience (Adults) 6.2 Clinical Studies Experience (Pediatrics) 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal/Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 CNS (Central Nervous System) 14.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) NOT FOR INTRATHECAL USE: Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits [see Warnings and Precautions (5.1)]. NSF: • Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. • Do not administer OMNISCAN to patients with: ○ chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or ○ acute kidney injury [see Contraindications (4)]. • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g., age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. • Do not exceed the recommended OMNISCAN dose and allow a sufficient period of time for elimination of the drug from the body prior to any readministration [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 CNS (Central Nervous System) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues [see Clinical Studies (14.1)]. 1.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 CNS (Central Nervous System) Adults: The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. Pediatric Patients (2-16 years): The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection [see Dosage and Administration (2.3)]. 2.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) Adult and Pediatric Patients (2-16 years of age): For imaging the kidney, the recommended dose of OMNISCAN is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) [see Dosage and Administration (2.3)]. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.3 Dosage Chart BODY WEIGHT kg lb PEDIATRIC 0.05 0.1 (mmol/kg) ADULTS 0.05 0.1 (mmol/kg) VOLUME (mL) VOLUME (mL) 12 26 1.2 2.4 - - 14 31 1.4 2.8 - - 16 35 1.6 3.2 - - 18 40 1.8 3.6 - - 20 44 2 4 - - 22 48 2.2 4.4 - - 24 53 2.4 4.8 - - 26 57 2.6 5.2 - - 28 62 2.8 5.6 - - 30 66 3 6 - - 40 88 4 8 4 8 50 110 5 10 5 10 60 132 6 12 6 12 70 154 7 14 7 14 80 176 8 16 8 16 90 198 - - 9 18 100 220 - - 10 20 110 242 - - 11 22 120 264 - - 12 24 130 286 - - 13 26 *The heaviest patient in clinical studies weighed 136 kg. 2.4 Dosing Guidelines Inspect OMNISCAN visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not use the solution if it is discolored or particulate matter is present. Draw OMNISCAN into the syringe and use immediately. Discard any unused portion of OMNISCAN Injection. To ensure complete delivery of the desired volume of contrast medium, follow the injection of OMNISCAN with a 5 mL flush of 0.9% sodium chloride. Complete the imaging procedure within 1 hour of administration of OMNISCAN. 2.5 Directions for Proper Use of OMNISCAN Pharmacy Bulk Package a. Use only a suitable work area, such as a laminar flow hood, to withdraw OMNISCAN Injection doses from the Pharmacy Bulk Package. b. Penetrate the Pharmacy Bulk Package container closure only once using a suitable transfer device and aseptic technique. c. Once the closure is penetrated, withdraw the container contents without delay. If delay is unavoidable, complete the fluid transfer as soon as possible within a maximum time of 8 hours. d. Once the closure is penetrated, keep the Pharmacy Bulk Package container in the aseptic area and at room temperature (do not exceed 30ºC). e. Following withdrawal of any dose from the Pharmacy Bulk Package, immediately label the dose with the supplied peel-off label that identifies the dose contents as OMNISCAN and that OMNISCAN is not for intrathecal use. f. Use each individual dose of OMNISCAN Injection immediately following withdrawal from the Pharmacy Bulk Package container; discard any unused portion of the OMNISCAN Injection dose not used immediately. g. Discard any unused OMNISCAN doses remaining in the Pharmacy Bulk Package 8 hours after the penetration of the container closure. 3 DOSAGE FORMS AND STRENGTHS Sterile aqueous solution for intravenous injection; 287 mg/mL. 4 CONTRAINDICATIONS OMNISCAN is contraindicated in patients with: • chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or • acute kidney injury • prior hypersensitivity reaction to OMNISCAN Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 WARNINGS AND PRECAUTIONS 5.1 Not for Intrathecal Use Inadvertent intrathecal use of OMNISCAN has occurred and caused convulsions, coma, sensory and motor neurologic deficits. 5.2 Nephrogenic Systemic Fibrosis Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. Do not administer OMNISCAN to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following OMNISCAN administration to GE Healthcare (1-800-654 0118) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. When administering OMNISCAN, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to any readministration [see Boxed Warning, Contraindications (4), Clinical Pharmacology (12.2) and Dosage and Administration (2)]. 5.3 Hypersensitivity Reactions Anaphylactoid and anaphylactic reactions, with cardiovascular, respiratory and/or cutaneous manifestations, resulting in death have occurred. Personnel trained in resuscitation techniques and resuscitation equipment should be present prior to OMNISCAN administration. If a hypersensitivity reaction occurs, stop OMNISCAN Injection and immediately begin appropriate therapy. Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after OMNISCAN Injection. 5.4 Acute Renal Failure In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of OMNISCAN Injection. The risk of renal failure may increase with increasing dose of gadolinium contrast. Use the lowest necessary dose of contrast and evaluate renal function in patients with renal insufficiency. Acute renal failure was observed in < 1% of patients in OMNISCAN clinical studies [see Adverse Reactions (6)]. OMNISCAN is cleared by glomerular filtration. Hemodialysis also enhances OMNISCAN clearance [see Use in Specific Populations (8.5, 8.6)]. 5.5 Impaired Visualization of Lesions Detectable with Non-contrast MRI Paramagnetic contrast agents such as OMNISCAN might impair the visualization of lesions which are seen on the non-contrast MRI. This may be due to effects of the paramagnetic contrast agent, or imaging parameters. Exercise caution when OMNISCAN MRI scans are interpreted in the absence of a companion non-contrast MRI. 5.6 Laboratory Test Findings Asymptomatic, transitory changes in serum iron have been observed. The clinical significance is unknown. OMNISCAN interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals, resulting in serum calcium concentrations lower than the true values. In patients with normal renal function, this effect lasts for 12-24 hours. In patients with decreased renal function, the interference with calcium measurements is expected to last during the prolonged elimination of OMNISCAN. After patients receive OMNISCAN, careful attention should be used in selecting the type of method used to measure calcium. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Nephrogenic systemic fibrosis [see Warnings and Precautions (5.2)] • Hypersensitivity reactions [see Warnings and Precautions (5.3)] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Clinical Studies Experience (Adults) In clinical studies 1160 patients were exposed to OMNISCAN. The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. The following adverse reactions occurred in 1% or less of patients: Application Site Disorders: Injection site reaction. Autonomic Nervous System Disorders: Vasodilation. Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope. Cardiovascular Disorders: Cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis. Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, paresthesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine. Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena. Hearing and Vestibular Disorders: Tinnitus. Liver and Biliary System Disorders: Abnormal hepatic function. Musculoskeletal System Disorders: Arthralgia, myalgia. Respiratory System Disorders: Rhinitis, dyspnea. Skin and Appendage Disorders: Pruritus, rash, erythematous rash, sweating increased, urticaria. Special Senses, Other Disorders: Taste loss, taste perversion. Urinary System Disorders: Acute reversible renal failure. Vision Disorders: Abnormal vision. 6.2 Clinical Studies Experience (Pediatrics) In the 97 pediatric patients in CNS studies with OMNISCAN [see Clinical Studies (14.1)] and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults. 6.3 Postmarketing Experience Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during the postmarketing use of OMNISCAN: Nervous System Disorders: Inadvertent intrathecal use causes seizures, coma, paresthesia, paresis. General Disorders: Nephrogenic Systemic Fibrosis (NSF) [see Warnings and Precautions (5.2)]. Renal and Urinary System Disorders: In patients with pre-existing renal insufficiency: acute renal failure, renal impairment, blood creatinine increased [see Warnings and Precautions (5.4)]. 7 DRUG INTERACTIONS Specific drug interaction studies have not been conducted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: OMNISCAN has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to OMNISCAN administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. Adequate and well controlled studies in pregnant women have not been conducted. OMNISCAN should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering OMNISCAN to a nursing woman. 8.4 Pediatric Use The safety and efficacy of OMNISCAN at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of OMNISCAN in adults, a pediatric CNS imaging study, and safety data in the scientific literature. However, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients. Pharmacokinetics of OMNISCAN have not been studied in pediatrics. The glomerular filtration rate of neonates and infants is much lower than that of adults. The pharmacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established. 8.5 Geriatric Use In clinical studies of OMNISCAN, 243 patients were between 65 and 80 years of age while 15 were over 80. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. OMNISCAN is excreted by the kidney, and the risk of toxic reactions to OMNISCAN is greater in patients with impaired renal function [see Warnings and Precautions (5.2, 5.4)]. Because elderly patients are more likely to have decreased renal function, select dose carefully and assess eGFR by laboratory testing before OMNISCAN use. 8.6 Renal/Hepatic Impairment Dose adjustments in renal or hepatic impairment have not been studied. Caution should be exercised in patients with impaired renal insufficiency [see Warnings and Precautions (5.2, 5.4)]. 10 OVERDOSAGE Clinical consequences of overdose with OMNISCAN have not been reported. The minimum lethal dose of intravenously administered OMNISCAN in rats and mice is greater than 20 mmol/kg (200 times the recommended human dose of 0.1 mmol/kg; 67 times the cumulative 0.3 mmol/kg dose). OMNISCAN is dialyzable. 11 DESCRIPTION OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection. OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution in a Pharmacy Bulk Package. A Pharmacy Bulk Package is used to dispense multiple single doses, utilizing a suitable transfer device. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymeth yl) 11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9•xH2O, and the following structural formula: Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pertinent physicochemical data for OMNISCAN are noted below: PARAMETER Osmolality (mOsmol/kg water) @ 37°C 789 Viscosity (cP) @ 20°C 2 @ 37°C 1.4 Density (g/mL) @ 25°C 1.14 Specific gravity @ 25°C 1.15 OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics In magnetic resonance imaging, visualization of normal and pathologic tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2). OMNISCAN is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent. By increasing the relaxation rate, OMNISCAN decreases both the T1 and T2 relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity. OMNISCAN does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e.g., cysts, mature postoperative scars). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of OMNISCAN in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of OMNISCAN in various lesions are not known. There is no detectable biotransformation or decomposition of gadodiamide. 12.3 Pharmacokinetics The pharmacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean ± SD) of 3.7 ± 2.7 minutes and 77.8 ± 16 minutes, respectively. Gadodiamide is eliminated primarily in the urine with 95.4 ± 5.5% (mean ± SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200 ± 61 mL/kg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro. Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long term animal studies have not been performed to evaluate the carcinogenic potential of gadodiamide. The results of the following genotoxicity assays were negative: in vitro bacterial reverse mutation assay, in vitro Chinese Hamster Ovary (CHO)/Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT) forward mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay at intravenous doses of 27 mmol/kg (approximately 7 times the maximum human dose based on a body surface area comparison). Impairment of male or female fertility was not observed in rats after intravenous administration three times per week at the maximum dose tested of 1.0 mmol/kg (approximately 0.5 times the maximum human dose based on a body surface area comparison). 14 CLINICAL STUDIES 14.1 CNS (Central Nervous System) OMNISCAN (0.1 mmol/kg) contrast enhancement in CNS MRI was evident in a study of 439 adults. In a study of sequential dosing, 57 adults received OMNISCAN 0.1 mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmol/kg). The MRIs were compared blindly. In 54/56 (96%) patients, OMNISCAN contrast enhancement was evident with both the 0.1 mmol/kg and cumulative 0.3 mmol/kg OMNISCAN doses relative to non-contrast MRI. In comparison to the non-contrast MRI, increased numbers of brain and spine lesions were noted in 42% of patients who received OMNISCAN at any dose. In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) OMNISCAN 0.1 mmol/kg dose provided more diagnostic value and in 30/56 (54%) the cumulative OMNISCAN 0.3 mmol/kg dose provided more diagnostic value. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The usefulness of a single 0.3 mmol/kg bolus in comparison to the cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) has not been established. OMNISCAN as a single 0.1 mmol/kg dose was evaluated in 97 pediatric patients with a mean age of 8.9 (2-18) years referred for CNS MRI. Postcontrast MRI provided added diagnostic information, diagnostic confidence, and new patient management information in 76%, 67%, and 52%, respectively, of pediatrics. 14.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN was evaluated in a controlled trial of 276 patients referred for body MRI. These patients had a mean age of 57 (9-88) years. Patients received 0.1 mmol/kg OMNISCAN for imaging the thorax (noncardiac), abdomen, and pelvic organs, or a dose of 0.05 mmol/kg for imaging the kidney. Pre- and post-OMNISCAN images were evaluated blindly for the degree of diagnostic value rated on a scale of “remarkably improved, improved, no change, worse, and cannot be determined.” The postcontrast results showed “remarkably improved” or “improved” diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients. In a dose ranging study 258 patients referred for body MRI received OMNISCAN 0.025, 0.05, 0.1 mmol/kg. The lowest effective dose of OMNISCAN for the kidney was 0.05 mmol/kg. 16 HOW SUPPLIED/STORAGE AND HANDLING OMNISCAN (gadodiamide) Injection is a sterile, clear, colorless to slightly yellow, aqueous solution containing 287 mg/mL of gadodiamide supplied in the following sizes: 100 mL in +PLUSPAK™ (polymer bottle), boxes of 10 Pharmacy Bulk Packages (NDC 0407-0690-70) SPECIAL HANDLING AND STORAGE FOR POLYMER BOTTLES. DO NOT USE IF TAMPER-EVIDENT RING IS BROKEN OR MISSING. Protect polymer bottles of OMNISCAN from strong daylight and direct exposure to sunlight. Do not freeze. Do not use if the product is inadvertently frozen. Store OMNISCAN at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP]. 17 PATIENT COUNSELING INFORMATION Patients receiving OMNISCAN should be instructed to inform their physician if they: • are pregnant or breast feeding, or • have a history of renal and/or liver disease, convulsions, asthma or allergic respiratory disorders, or recent administration of gadolinium-based contrast. GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF: • Describe the clinical manifestations of NSF • Describe procedures to screen for the detection of renal impairment Instruct the patients to contact their physician if they develop signs or symptoms of NSF following OMNISCAN administration such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; or muscle weakness. Distributed by GE Healthcare Inc., Princeton, NJ Manufactured by GE Healthcare Ireland, Cork, Ireland OMNISCAN is a trademark of GE Healthcare. GE and the GE Monogram are trademarks of General Electric Company. © 2013 General Electric Company - All rights reserved. Reference ID: 3364061 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:47.532685	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022066s00420123s039lbl.pdf', 'application_number': 20123, 'submission_type': 'SUPPL ', 'submission_number': 39}
12,236	ACCURETIC (quinapril HCl/hydrochlorothiazide) Tablets WARNING: FETAL TOXICITY  When pregnancy is detected, discontinue ACCURETIC as soon as possible.  Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity DESCRIPTION ACCURETIC is a fixed-combination tablet that combines an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride, and a thiazide diuretic, hydrochlorothiazide. Quinapril hydrochloride is chemically described as [3S-[2[R(R)], 3R*]]-2-[2-[[1 (ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3 isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5. HCl and its structural formula is: structural formula Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. 1 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hydrochlorothiazide is chemically described as: 6-Chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8CIN3O4S2 and its structural formula is: structural formula Hydrochlorothiazide is a white to off-white, crystalline powder which is slightly soluble in water but freely soluble in sodium hydroxide solution. ACCURETIC is available for oral use as fixed combination tablets in three strengths of quinapril with hydrochlorothiazide: 10 mg with 12.5 mg (ACCURETIC 10/12.5), 20 mg with 12.5 mg (ACCURETIC 20/12.5), and 20 mg with 25 mg (ACCURETIC 20/25). Inactive ingredients: candelilla wax, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. CLINICAL PHARMACOLOGY Mechanism of Action: The principal metabolite of quinapril, quinaprilat, is an inhibitor of ACE activity in human subjects and animals. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine, or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with quinapril alone resulted in mean increases in potassium of 0.07 mmol/L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). 2 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in non-blacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldolsterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown. Pharmacokinetics and Metabolism: The rate and extent of absorption of quinapril and hydrochlorothiazide from ACCURETIC tablets are not different, respectively, from the rate and extent of absorption of quinapril and hydrochlorothiazide from immediate-release monotherapy formulations, either administered concurrently or separately. Following oral administration of Accupril (quinapril monotherapy) tablets, peak plasma quinapril concentrations are observed within 1 hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and more complete (50% to 80%). The rate of quinapril absorption was reduced by 14% when ACCURETIC tablets were administered with a high-fat meal as compared to fasting, while the extent of absorption was not affected. The rate of hydrochlorothiazide absorption was reduced by 12% when ACCURETIC tablets were administered with a high-fat meal, while the extent of absorption was not significantly affected. Therefore, ACCURETIC may be administered without regard to food. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral 3 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dosing of quinapril, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours postdose. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6 to 7.8 L/kg, consistent with measured plasma protein binding of 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6 to 1.8 times those measured in plasma. Some placental passage occurred when quinapril was administered to pregnant rats. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. Hydrochlorothiazide crosses the placenta freely but not the blood-brain barrier. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat is reduced in elderly patients (65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5 to 80-mg doses and 40- to 160-mg in multiple daily doses. Pharmacodynamics and Clinical Effects: Single doses of 20 mg of quinapril provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20-mg dose giving 75% inhibition for about 4 hours, 4 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 to 80 mg. Administration of 10 to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted (see WARNINGS). Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks. In multiple-dose studies, 10 to 80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5 to 11/3 to 7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice-daily dosing tended to give a somewhat lower trough blood pressure than once-daily dosing with the same total dose. The antihypertensive effect of quinapril continues during long-term therapy, with no evidence of loss of effectiveness. Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. Therapeutic effects of quinapril appear to be the same for elderly (65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. In patients with hypertension, quinapril 10 to 40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Use of quinapril with a thiazide diuretic gives blood pressure lowering effect greater than that seen with either agent alone. In clinical trials of quinapril/hydrochlorothiazide using quinapril doses of 2.5 to 40 mg and 5 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects were sustained for at least 24 hours, and increased with increasing dose of either component. Although quinapril monotherapy is somewhat less effective in blacks than in non-blacks, the efficacy of combination therapy appears to be independent of race. By blocking the renin angiotensin-aldosterone axis, administration of quinapril tends to reduce the potassium loss associated with the diuretic. In clinical trials of ACCURETIC, the average change in serum potassium was near zero when 2.5 to 40 mg of quinapril was combined with hydrochlorothiazide 6.25 mg, and the average subject who received 10 to 20/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. INDICATIONS AND USAGE ACCURETIC is indicated for the treatment of hypertension. This fixed combination is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION). In using ACCURETIC, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that quinapril does not have a similar risk (see WARNINGS: Neutropenia/Agranulocytosis). Angioedema in Black Patients: Black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks. It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. CONTRAINDICATIONS ACCURETIC is contraindicated in patients who are hypersensitive to quinapril or hydrochlorothiazide and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. Because of the hydrochlorothiazide components, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. 6 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not co-administer ACCURETIC with aliskiren:  in patients with diabetes WARNINGS Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin converting inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including quinapril) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving quinapril. In two similarly sized US postmarketing quinapril trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in Study 1 and 2, respectively) and 0.39% and 0.17% of non-blacks. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with ACCURETIC should be discontinued immediately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE REACTIONS). Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE 7 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients With a History of Angioedema: Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also CONTRAINDICATIONS). Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with Hymenoptera venom while receiving ACE inhibitors sustained life- threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent challenge. Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Hypotension: ACCURETIC can cause symptomatic hypotension, probably not more frequently than either monotherapy. It was reported in 1.2% of 1,571 patients receiving ACCURETIC during clinical trials. Like other ACE inhibitors, quinapril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension sometimes associated with oliguria and/or progressive azotemia, and rarely acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis or severe volume and/or salt depletion of any etiology. Volume and/or salt depletion should be corrected before initiating therapy with ACCURETIC. 8 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ACCURETIC should be used cautiously in patients receiving concomitant therapy with other antihypertensives. The thiazide component of ACCURETIC may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patients. In patients at risk of excessive hypotension, therapy with ACCURETIC should be started under close medical supervision. Such patients should be followed closely for the first 2 weeks of treatment and whenever the dosage of quinapril or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. If excessive hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of normal saline. ACCURETIC treatment usually can be continued following restoration of blood pressure and volume. If symptomatic hypotension develops, a dose reduction or discontinuation of ACCURETIC may be necessary. Impaired Renal Function: ACCURETIC should be used with caution in patients with severe renal disease. Thiazides may precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative. When the renin-angiotensin-aldosterone system is inhibited by quinapril, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin aldosterone system, treatment with angiotensin-converting enzyme inhibitors (including quinapril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral renal artery stenosis, treatment with ACE inhibitors was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of ACE inhibitor, concomitant diuretic, or both. When such patients are treated with ACCURETIC, renal function should be monitored during the first few weeks of therapy. 9 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some quinapril-treated hypertensive patients with no apparent preexisting renal vascular diseases have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ACCURETIC may be required. Evaluation of the hypertensive patients should also include assessment of the renal function (see DOSAGE AND ADMINISTRATION). Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. Available data from clinical trials of quinapril are insufficient to show that, in patients without prior reactions to other ACE inhibitors, quinapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. 10 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ACCURETIC as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ACCURETIC, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to ACCURETIC for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use). Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that occurred in adults. No teratogenic effects of quinapril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. No teratogenic effects of ACCURETIC were seen in studies of pregnant rats and rabbits. On a mg/kg (quinapril/hydrochlorothiazide) basis, the doses used were up to 188/94 times (in rats) and 0.6/0.3 times (in rabbits) the maximum recommended human dose. 11 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Impaired Hepatic Function: ACCURETIC should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterases, patients with impaired liver function could develop markedly elevated plasma levels of quinapril. No normal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. PRECAUTIONS General Serum Electrolyte Abnormalities: In clinical trials, hyperkalemia (serum potassium 5.8 mmol/L) occurred in approximately 2% of patients receiving quinapril. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. The risk of hyperkalemia may be increased in patients with renal insufficiency, diabetes mellitus or with concomitant use of drugs that raise serum potassium (see Drug Interactions). The risk of hypokalemia 12 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may be increased in patients with cirrhosis, brisk diuresis, or with concomitant use of drugs that lower serum potassium. Monitor serum electrolytes periodically. Other Metabolic Disturbances: Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving ACCURETIC. Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, quinapril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Information for Patients Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients receiving ACCURETIC should be told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until after consulting with the prescribing physician. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACCURETIC during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. 13 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Symptomatic Hypotension: A patient receiving ACCURETIC should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patient should be told that if syncope occurs, ACCURETIC should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the same consequences of lightheadedness and possible syncope. Patients planning to undergo major surgery and/ or general or spinal anesthesia should be told to inform their physicians that they are taking an ACE inhibitor. Hyperkalemia: A patient receiving ACCURETIC should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia. NOTE: As with many other drugs, certain advice to patients being treated with quinapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Laboratory Tests The hydrochlorothiazide component of ACCURETIC may decrease serum PBI levels without signs of thyroid disturbance. Therapy with ACCURETIC should be interrupted for a few days before carrying out tests of parathyroid function. Drug Interactions Potassium Supplements and Potassium-Sparing Diuretics: Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase 14 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the risk of hyperkalemia. If concomitant use of such agents is indicated, monitor serum potassium frequently. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with ACCURETIC, a thiazide diuretic is coadministered with the ACE inhibitor. ACCURETIC and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on ACCURETIC and other agents that affect the RAS. Do not co-administer aliskiren with ACCURETIC in patients with diabetes. Avoid concomitant use of aliskiren with ACCURETIC in patients with renal impairment (GFR <60 mL/min/1.73 m2). Tetracycline and Other Drugs That Interact with Magnesium: Simultaneous administration of tetracycline with quinapril reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in quinapril tablets. This interaction should be considered if coprescribing quinapril and tetracycline or other drugs that interact with magnesium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of 15 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs. Agents that inhibit mTOR: Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. Other Agents: Drug interaction studies of quinapril and other agents showed:  Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of quinapril.  The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice daily.  Digoxin: Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (See PRECAUTIONS).  No pharmacokinetic interaction was observed when single doses of quinapril and hydrochlorothiazide were administered concomitantly. When administered concurrently, the following drugs may interact with thiazide diuretics.  Alcohol, Barbiturates, or Narcotics—potentiation of orthostatic hypotension may occur.  Antidiabetic Drugs (oral hypoglycemic agents and insulin)—dosage adjustments of the antidiabetic drug may be required (See PRECAUTIONS).  Cholestyramine and Colestipol Resin—absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. 16 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Corticosteroids, ACTH—intensified electrolyte depletion, particularly hypokalemia.  Pressor Amines (e.g., norepinephrine)—possible decreased response to pressor amines, but not sufficient to preclude their therapeutic use.  Skeletal Muscle Relaxants, Nondepolarizing (e.g., tubocurarine)—possible increased responsiveness to the muscle relaxant.  Non-steroidal Anti-inflammatory Drugs—the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted in animals with ACCURETIC. Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 or 60 times the maximum human daily dose, respectively, on a mg/kg basis and 3.8 or 10 times the maximum human daily dose on a mg/m2 basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively). Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was “equivocal” evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese hamster ovary (CHO) test for chromosomal aberrations; or in vivo assays using mouse germinal cell chromosomes, Chinese hamster 17 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) test and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1300 µg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diets, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Nursing Mothers Because quinapril and hydrochlorothiazide are secreted in human milk, caution should be exercised when ACCURETIC is administered to a nursing woman. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of quinapril in infants, a decision should be made whether to discontinue nursing or to discontinue ACCURETIC, taking into account the importance of the drug to the mother. Geriatric Use Clinical studies of quinapril HCl/hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Pediatric Use Neonates with a history of in utero exposure to ACCURETIC: 18 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Removal of quinapril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means. Safety and effectiveness of ACCURETIC in children have not been established. ADVERSE REACTIONS ACCURETIC has been evaluated for safety in 1571 patients in controlled and uncontrolled studies. Of these, 498 were given quinapril plus hydrochlorothiazide for at least 1 year, with 153 patients extending combination therapy for over 2 years. In clinical trials with ACCURETIC, no adverse experience specific to the combination has been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with quinapril or hydrochlorothiazide. Adverse experiences were usually mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy because of adverse effects was required in 2.1% in patients in controlled studies. The most common reasons for discontinuation of therapy with ACCURETIC were cough (1.0%; see PRECAUTIONS) and headache (0.7%). Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 943 patients treated with quinapril plus hydrochlorothiazide in controlled trials are shown below. 19 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Percent of Patients in Controlled Trials Quinapril/HCTZ Placebo N = 943 N = 100 Headache 6.7 30.0 Dizziness 4.8 4.0 Coughing 3.2 2.0 Fatigue 2.9 3.0 Myalgia 2.4 5.0 Viral Infection 1.9 4.0 Rhinitis 2.0 3.0 Nausea and/or Vomiting 1.8 6.0 Abdominal Pain 1.7 4.0 Back Pain 1.5 2.0 Diarrhea 1.4 1.0 Upper Respiratory Infection 1.3 4.0 Insomnia 1.2 2.0 Somnolence 1.2 0.0 Bronchitis 1.2 1.0 Dyspepsia 1.2 2.0 Asthenia 1.1 1.0 Pharyngitis 1.1 2.0 Vasodilatation 1.0 1.0 Vertigo 1.0 2.0 Chest Pain 1.0 2.0 Clinical adverse experiences probably, possibly, or definitely related or of uncertain relationship to therapy occurring in 0.5% to <1.0% (except as noted) of the patients treated with quinapril/HCTZ in controlled and uncontrolled trials (N=1571) and less frequent, clinically significant events seen in clinical trials or postmarketing experience (the rarer events are in italics) include (listed by body system): BODY AS A WHOLE: Asthenia, Malaise CARDIOVASCULAR: Palpitation, Tachycardia, Heart Failure, Hyperkalemia, Myocardial Infarction, Cerebrovascular Accident, Hypertensive Crisis, Angina Pectoris, Orthostatic Hypotension, Cardiac Rhythm Disturbance GASTROINTESTINAL: Mouth or Throat Dry, Gastrointestinal Hemorrhage, Pancreatitis, Abnormal Liver Function Tests NERVOUS/PSYCHIATRIC: Nervousness, Vertigo, Paresthesia RESPIRATORY: Sinusitis, Dyspnea 20 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INTEGUMENTARY: Pruritus, Sweating Increased, Erythema Multiforme, Exfoliative Dermatitis, Photosensitivity Reaction, Alopecia, Pemphigus UROGENITAL SYSTEM: Acute Renal Failure, Impotence OTHER: Agranulocytosis, Thrombocytopenia, Arthralgia Angioedema: Angioedema has been reported in 0.1% of patients receiving quinapril (0.1%) (see WARNINGS). Postmarketing Experience The following serious nonfatal adverse events, regardless of their relationship to quinapril and HCTZ combination tablets, have been reported during extensive postmarketing experience: BODY AS A WHOLE: Shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, hernia and anaphylactoid reaction. CARDIOVASCULAR SYSTEM: Bradycardia, cor pulmonale, vasculitis, and deep thrombosis. DIGESTIVE SYSTEM: Gastrointestinal carcinoma, cholestatic jaundice, hepatitis, esophagitis, vomiting, and diarrhea. EYE DISORDERS: acute myopia and acute angle closure glaucoma (see WARNINGS). HEMIC SYSTEM: Anemia. METABOLIC AND NUTRITIONAL DISORDERS: Weight loss. MUSCULOSKELETAL SYSTEM: Myopathy, myositis, and arthritis. NERVOUS SYSTEM: Paralysis, hemiplegia, speech disorder, abnormal gait, meningism, and amnesia. RESPIRATORY SYSTEM: Pneumonia, asthma, respiratory infiltration, and lung disorder. 21 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SKIN AND APPENDAGES: Urticaria, macropapular rash, and petechiases. SPECIAL SENSES: Abnormal vision. UROGENITAL SYSTEM: Kidney function abnormal, albuminuria, pyuria, hematuria, and nephrosis. Quinapril monotherapy has been evaluated for safety in 4960 patients. In clinical trials adverse events which occurred with quinapril were also seen with ACCURETIC. In addition, the following were reported for quinapril at an incidence >0.5%: depression, back pain, constipation, syncope, and amblyopia. Hydrochlorothiazide has been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency. 22 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BODY AS A WHOLE: Weakness. CARDIOVASCULAR: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics). DIGESTIVE: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia. NEUROLOGIC: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. MUSCULOSKELETAL: Muscle spasm. HEMATOLOGIC: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and hemolytic anemia. RENAL: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS). METABOLIC: Hyperglycemia, glycosuria, and hyperuricemia. HYPERSENSITIVITY: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Clinical Laboratory Test Findings Serum Electrolytes: See PRECAUTIONS. Creatinine, Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4%, respectively, of patients treated with ACCURETIC. Most increases were minor and reversible, which can occur in patients with essential hypertension but most frequently in patients with renal artery stenosis (see PRECAUTIONS). PBI and Tests of Parathyroid Function: See PRECAUTIONS. Hematology: See WARNINGS. Other (causal relationships unknown): Other clinically important changes in standard laboratory tests were rarely associated with ACCURETIC administration. Elevations in uric 23 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda acid, glucose, magnesium, cholesterol, triglyceride, and calcium (see PRECAUTIONS) have been reported. OVERDOSAGE No specific information is available on the treatment of overdosage with ACCURETIC or quinapril monotherapy; treatment should be symptomatic and supportive. Therapy with ACCURETIC should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures. The oral median lethal dose of quinapril/hydrochlorothiazide in combination ranges from 1063/664 to 4640/2896 mg/kg in mice and rats. Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats. In single-dose studies of hydrochlorothiazide, most rats survived doses up to 2.75 g/kg. Data from human overdoses of ACE inhibitors are scanty; the most likely manifestation of human quinapril overdosage is hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of quinapril and its metabolites. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution. 24 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION As individual monotherapy, quinapril is an effective treatment of hypertension in once- daily doses of 10 to 80 mg and hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of quinapril/hydrochlorothiazide combination therapy using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing dose of either component. The side effects (see WARNINGS) of quinapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of quinapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens that combine low doses of hydrochlorothiazide with quinapril produce minimal effects on serum potassium. In clinical trials of ACCURETIC, the average change in serum potassium was near zero in subjects who received HCTZ 6.25 mg in the combination, and the average subject who received 10 to 40/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Therapy Guided by Clinical Effect Patients whose blood pressures are not adequately controlled with quinapril monotherapy may instead be given ACCURETIC 10/12.5 or 20/12.5. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve blood pressure control with less electrolyte disturbance if they are switched to ACCURETIC 10/12.5 or 20/12.5. 25 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Replacement Therapy For convenience, patients who are adequately treated with 20 mg of quinapril and 25 mg of hydrochlorothiazide and experience no significant electrolyte disturbances may instead wish to receive ACCURETIC 20/25. Use in Renal Impairment Regimens of therapy with ACCURETIC need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73 m2 (serum creatinine roughly 3 mg/dL or 265 mol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides. Therefore, ACCURETIC is not recommended for use in these patients. HOW SUPPLIED ACCURETIC is available in tablets of three different strengths: 10/12.5 tablets: pink, scored elliptical, biconvex, film-coated tablets coded “PD 222” on one side. Each tablet contains 10 mg of quinapril and 12.5 mg of hydrochlorothiazide. NDC 0071-0222-23: 90 tablet bottles 20/12.5 tablets: pink, scored triangular, film-coated tablets coded “PD 220” on one side. Each tablet contains 20 mg of quinapril and 12.5 mg of hydrochlorothiazide. NDC 0071-0220-23: 90 tablet bottles 20/25 tablets: pink, round, biconvex, film-coated tablets coded “PD 223” on one side. Each tablet contains 20 mg of quinapril and 25 mg of hydrochlorothiazide. NDC 0071-0223-23: 90 tablet bottles Dispense in tight containers as defined in the USP. Store at Controlled Room Temperature 20–25C (68–77F) [see USP]. 26 Reference ID: 3499654 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0216-14.x Revised May 2014 Reference ID: 3499654 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:47.689921	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020125s018lbl.pdf', 'application_number': 20125, 'submission_type': 'SUPPL ', 'submission_number': 18}
12,237	ACCURETIC (quinapril HCl/hydrochlorothiazide) Tablets WARNING: FETAL TOXICITY  When pregnancy is detected, discontinue ACCURETIC as soon as possible.  Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity DESCRIPTION ACCURETIC is a fixed-combination tablet that combines an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride, and a thiazide diuretic, hydrochlorothiazide. Quinapril hydrochloride is chemically described as [3S-[2[R(R)], 3R*]]-2-[2-[[1 (ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3 isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5. HCl and its structural formula is: structural formula Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. 1 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hydrochlorothiazide is chemically described as: 6-Chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8CIN3O4S2 and its structural formula is: structural formula Hydrochlorothiazide is a white to off-white, crystalline powder which is slightly soluble in water but freely soluble in sodium hydroxide solution. ACCURETIC is available for oral use as fixed combination tablets in three strengths of quinapril with hydrochlorothiazide: 10 mg with 12.5 mg (ACCURETIC 10/12.5), 20 mg with 12.5 mg (ACCURETIC 20/12.5), and 20 mg with 25 mg (ACCURETIC 20/25). Inactive ingredients: candelilla wax, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. CLINICAL PHARMACOLOGY Mechanism of Action: The principal metabolite of quinapril, quinaprilat, is an inhibitor of ACE activity in human subjects and animals. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine, or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with quinapril alone resulted in mean increases in potassium of 0.07 mmol/L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). 2 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in non-blacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldolsterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown. Pharmacokinetics and Metabolism: The rate and extent of absorption of quinapril and hydrochlorothiazide from ACCURETIC tablets are not different, respectively, from the rate and extent of absorption of quinapril and hydrochlorothiazide from immediate-release monotherapy formulations, either administered concurrently or separately. Following oral administration of Accupril (quinapril monotherapy) tablets, peak plasma quinapril concentrations are observed within 1 hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and more complete (50% to 80%). The rate of quinapril absorption was reduced by 14% when ACCURETIC tablets were administered with a high-fat meal as compared to fasting, while the extent of absorption was not affected. The rate of hydrochlorothiazide absorption was reduced by 12% when ACCURETIC tablets were administered with a high-fat meal, while the extent of absorption was not significantly affected. Therefore, ACCURETIC may be administered without regard to food. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral 3 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dosing of quinapril, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours postdose. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6 to 7.8 L/kg, consistent with measured plasma protein binding of 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6 to 1.8 times those measured in plasma. Some placental passage occurred when quinapril was administered to pregnant rats. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. Hydrochlorothiazide crosses the placenta freely but not the blood-brain barrier. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat is reduced in elderly patients (65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5- to 80-mg doses and 40- to 160-mg in multiple daily doses. Pharmacodynamics and Clinical Effects: Single doses of 20 mg of quinapril provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20-mg dose giving 75% inhibition for about 4 hours, 4 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 to 80 mg. Administration of 10 to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted (see WA R N I N G S ). Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks. In multiple-dose studies, 10 to 80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5 to 11/3 to 7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice-daily dosing tended to give a somewhat lower trough blood pressure than once-daily dosing with the same total dose. The antihypertensive effect of quinapril continues during long-term therapy, with no evidence of loss of effectiveness. Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. Therapeutic effects of quinapril appear to be the same for elderly (65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. In patients with hypertension, quinapril 10 to 40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Use of quinapril with a thiazide diuretic gives blood pressure lowering effect greater than that seen with either agent alone. In clinical trials of quinapril/hydrochlorothiazide using quinapril doses of 2.5 to 40 mg and 5 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects were sustained for at least 24 hours, and increased with increasing dose of either component. Although quinapril monotherapy is somewhat less effective in blacks than in non-blacks, the efficacy of combination therapy appears to be independent of race. By blocking the renin angiotensin-aldosterone axis, administration of quinapril tends to reduce the potassium loss associated with the diuretic. In clinical trials of ACCURETIC, the average change in serum potassium was near zero when 2.5 to 40 mg of quinapril was combined with hydrochlorothiazide 6.25 mg, and the average subject who received 10 to 20/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. INDICATIONS AND USAGE Hypertension: ACCURETIC is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with ACCURETIC. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. 6 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. This fixed combination is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION). In using ACCURETIC, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that quinapril does not have a similar risk (see WARNINGS: Neutropenia/Agranulocytosis). Angioedema in Black Patients: Black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks. It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. CONTRAINDICATIONS ACCURETIC is contraindicated in patients who are hypersensitive to quinapril or hydrochlorothiazide and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. Because of the hydrochlorothiazide components, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. 7 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not co-administer ACCURETIC with aliskiren:  in patients with diabetes. WARNINGS Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin converting inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including quinapril) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving quinapril. In two similarly sized US postmarketing quinapril trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in Study 1 and 2, respectively) and 0.39% and 0.17% of non-blacks. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with ACCURETIC should be discontinued immediately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE REACTIONS). Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE 8 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients With a History of Angioedema: Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also CONTRAINDICATIONS). Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with Hymenoptera venom while receiving ACE inhibitors sustained life- threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent challenge. Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Hypotension: ACCURETIC can cause symptomatic hypotension, probably not more frequently than either monotherapy. It was reported in 1.2% of 1,571 patients receiving ACCURETIC during clinical trials. Like other ACE inhibitors, quinapril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension sometimes associated with oliguria and/or progressive azotemia, and rarely acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis or severe volume and/or salt depletion of any etiology. Volume and/or salt depletion should be corrected before initiating therapy with ACCURETIC. 9 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ACCURETIC should be used cautiously in patients receiving concomitant therapy with other antihypertensives. The thiazide component of ACCURETIC may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patients. In patients at risk of excessive hypotension, therapy with ACCURETIC should be started under close medical supervision. Such patients should be followed closely for the first 2 weeks of treatment and whenever the dosage of quinapril or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. If excessive hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of normal saline. ACCURETIC treatment usually can be continued following restoration of blood pressure and volume. If symptomatic hypotension develops, a dose reduction or discontinuation of ACCURETIC may be necessary. Impaired Renal Function: ACCURETIC should be used with caution in patients with severe renal disease. Thiazides may precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative. When the renin-angiotensin-aldosterone system is inhibited by quinapril, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin aldosterone system, treatment with angiotensin-converting enzyme inhibitors (including quinapril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral renal artery stenosis, treatment with ACE inhibitors was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of ACE inhibitor, concomitant diuretic, or both. When such patients are treated with ACCURETIC, renal function should be monitored during the first few weeks of therapy. 10 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Some quinapril-treated hypertensive patients with no apparent preexisting renal vascular diseases have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ACCURETIC may be required. Evaluation of the hypertensive patients should also include assessment of the renal function (see DOSAGE AND ADMINISTRATION). Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. Available data from clinical trials of quinapril are insufficient to show that, in patients without prior reactions to other ACE inhibitors, quinapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ACCURETIC as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. 11 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ACCURETIC, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to ACCURETIC for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use). Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that occurred in adults. No teratogenic effects of quinapril were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. No teratogenic effects of ACCURETIC were seen in studies of pregnant rats and rabbits. On a mg/kg (quinapril/hydrochlorothiazide) basis, the doses used were up to 188/94 times (in rats) and 0.6/0.3 times (in rabbits) the maximum recommended human dose. Impaired Hepatic Function: ACCURETIC should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterases, patients with impaired liver function could develop markedly elevated plasma levels of quinapril. No normal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to 12 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. PRECAUTIONS General Serum Electrolyte Abnormalities: In clinical trials, hyperkalemia (serum potassium 5.8 mmol/L) occurred in approximately 2% of patients receiving quinapril. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of other drugs that raise serum potassium levels. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. The risk of hyperkalemia may be increased in patients with renal insufficiency, diabetes mellitus or with concomitant use of drugs that raise serum potassium (see Drug Interactions). The risk of hypokalemia may be increased in patients with cirrhosis, brisk diuresis, or with concomitant use of drugs that lower serum potassium. Monitor serum electrolytes periodically. Other Metabolic Disturbances: Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving ACCURETIC. Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, resolving after 13 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, quinapril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Information for Patients Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Tell patients receiving ACCURETIC to immediately report any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to temporarily discontinue Accuretic until after consulting with the prescribing physician. Pregnancy: Tell female patients of childbearing age about the consequences of exposure to ACCURETIC during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible. Symptomatic Hypotension: Tell patients receiving ACCURETIC that lightheadedness can occur, especially during the first days of therapy, and to report it to the prescribing physician. Tell the patient if syncope occurs, discontinue ACCURETIC until the physician has been consulted. Tell patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the same consequences of lightheadedness and possible syncope. Tell patients planning to undergo major surgery and/ or general or spinal anesthesia to inform their physicians that they are taking an ACE inhibitor. Hyperkalemia: Tell patients receiving ACCURETIC not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. 14 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Neutropenia: Tell patients to promptly report any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia. NOTE: As with many other drugs, certain advice to patients being treated with quinapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Laboratory Tests The hydrochlorothiazide component of ACCURETIC may decrease serum PBI levels without signs of thyroid disturbance. Therapy with ACCURETIC should be interrupted for a few days before carrying out tests of parathyroid function. Drug Interactions Agents Increasing Serum Potassium: Coadministration of ACCURETIC with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with ACCURETIC, a thiazide diuretic is coadministered with the ACE inhibitor. ACCURETIC and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on ACCURETIC and other agents that affect the RAS. 15 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not co-administer aliskiren with ACCURETIC in patients with diabetes. Avoid concomitant use of aliskiren with ACCURETIC in patients with renal impairment (GFR <60 mL/min/1.73 m2). Tetracycline and Other Drugs That Interact with Magnesium: Simultaneous administration of tetracycline with quinapril reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in quinapril tablets. This interaction should be considered if coprescribing quinapril and tetracycline or other drugs that interact with magnesium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by NSAIDs. Agents that inhibit mTOR: Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. Other Agents: Drug interaction studies of quinapril and other agents showed:  Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics of single doses of quinapril. 16 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not significantly changed by quinapril coadministration twice daily.  Digoxin: Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (See PRECAUTIONS).  No pharmacokinetic interaction was observed when single doses of quinapril and hydrochlorothiazide were administered concomitantly. When administered concurrently, the following drugs may interact with thiazide diuretics.  Alcohol, Barbiturates, or Narcotics—potentiation of orthostatic hypotension may occur.  Antidiabetic Drugs (oral hypoglycemic agents and insulin)—dosage adjustments of the antidiabetic drug may be required (See PRECAUTIONS).  Cholestyramine and Colestipol Resin—absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.  Corticosteroids, ACTH—intensified electrolyte depletion, particularly hypokalemia.  Pressor Amines (e.g., norepinephrine)—possible decreased response to pressor amines, but not sufficient to preclude their therapeutic use.  Skeletal Muscle Relaxants, Nondepolarizing (e.g., tubocurarine)—possible increased responsiveness to the muscle relaxant.  Non-steroidal Anti-inflammatory Drugs—the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents. 17 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted in animals with ACCURETIC. Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 or 60 times the maximum human daily dose, respectively, on a mg/kg basis and 3.8 or 10 times the maximum human daily dose on a mg/m2 basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively). Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was “equivocal” evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese hamster ovary (CHO) test for chromosomal aberrations; or in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) test and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1300 µg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diets, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. 18 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers Because quinapril and hydrochlorothiazide are secreted in human milk, caution should be exercised when ACCURETIC is administered to a nursing woman. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of quinapril in infants, a decision should be made whether to discontinue nursing or to discontinue ACCURETIC, taking into account the importance of the drug to the mother. Geriatric Use Clinical studies of quinapril HCl/hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Pediatric Use Neonates with a history of in utero exposure to ACCURETIC: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Removal of quinapril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means. Safety and effectiveness of ACCURETIC in children have not been established. ADVERSE REACTIONS ACCURETIC has been evaluated for safety in 1571 patients in controlled and uncontrolled studies. Of these, 498 were given quinapril plus hydrochlorothiazide for at least 1 year, 19 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with 153 patients extending combination therapy for over 2 years. In clinical trials with ACCURETIC, no adverse experience specific to the combination has been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with quinapril or hydrochlorothiazide. Adverse experiences were usually mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy because of adverse effects was required in 2.1% in patients in controlled studies. The most common reasons for discontinuation of therapy with ACCURETIC were cough (1.0%; see PRECAUTIONS) and headache (0.7%). Adverse experiences probably or possibly related to therapy or of unknown relationship to therapy occurring in 1% or more of the 943 patients treated with quinapril plus hydrochlorothiazide in controlled trials are shown below. Percent of Patients in Controlled Trials Quinapril/HCTZ Placebo N = 943 N = 100 Headache 6.7 30.0 Dizziness 4.8 4.0 Coughing 3.2 2.0 Fatigue 2.9 3.0 Myalgia 2.4 5.0 Viral Infection 1.9 4.0 Rhinitis 2.0 3.0 Nausea and/or Vomiting 1.8 6.0 Abdominal Pain 1.7 4.0 Back Pain 1.5 2.0 Diarrhea 1.4 1.0 Upper Respiratory Infection 1.3 4.0 Insomnia 1.2 2.0 Somnolence 1.2 0.0 Bronchitis 1.2 1.0 Dyspepsia 1.2 2.0 Asthenia 1.1 1.0 Pharyngitis 1.1 2.0 Vasodilatation 1.0 1.0 Vertigo 1.0 2.0 Chest Pain 1.0 2.0 Clinical adverse experiences probably, possibly, or definitely related or of uncertain relationship to therapy occurring in 0.5% to <1.0% (except as noted) of the patients treated with quinapril/HCTZ in controlled and uncontrolled trials (N=1571) and less 20 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda frequent, clinically significant events seen in clinical trials or postmarketing experience (the rarer events are in italics) include (listed by body system): BODY AS A WHOLE: Asthenia, Malaise CARDIOVASCULAR: Palpitation, Tachycardia, Heart Failure, Hyperkalemia, Myocardial Infarction, Cerebrovascular Accident, Hypertensive Crisis, Angina Pectoris, Orthostatic Hypotension, Cardiac Rhythm Disturbance GASTROINTESTINAL: Mouth or Throat Dry, Gastrointestinal Hemorrhage, Pancreatitis, Abnormal Liver Function Tests NERVOUS/PSYCHIATRIC: Nervousness, Vertigo, Paresthesia RESPIRATORY: Sinusitis, Dyspnea INTEGUMENTARY: Pruritus, Sweating Increased, Erythema Multiforme, Exfoliative Dermatitis, Photosensitivity Reaction, Alopecia, Pemphigus UROGENITAL SYSTEM: Acute Renal Failure, Impotence OTHER: Agranulocytosis, Thrombocytopenia, Arthralgia Angioedema: Angioedema has been reported in 0.1% of patients receiving quinapril (0.1%) (see WARNINGS). Postmarketing Experience The following serious nonfatal adverse events, regardless of their relationship to quinapril and HCTZ combination tablets, have been reported during extensive postmarketing experience: BODY AS A WHOLE: Shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, hernia and anaphylactoid reaction. CARDIOVASCULAR SYSTEM: Bradycardia, cor pulmonale, vasculitis, and deep thrombosis. 21 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIGESTIVE SYSTEM: Gastrointestinal carcinoma, cholestatic jaundice, hepatitis, esophagitis, vomiting, and diarrhea. EYE DISORDERS: Acute myopia and acute angle closure glaucoma (see WARNINGS). HEMIC SYSTEM: Anemia. METABOLIC AND NUTRITIONAL DISORDERS: Weight loss. MUSCULOSKELETAL SYSTEM: Myopathy, myositis, and arthritis. NERVOUS SYSTEM: Paralysis, hemiplegia, speech disorder, abnormal gait, meningism, and amnesia. RESPIRATORY SYSTEM: Pneumonia, asthma, respiratory infiltration, and lung disorder. SKIN AND APPENDAGES: Urticaria, macropapular rash, and petechiases. SPECIAL SENSES: Abnormal vision. UROGENITAL SYSTEM: Kidney function abnormal, albuminuria, pyuria, hematuria, and nephrosis. Quinapril monotherapy has been evaluated for safety in 4960 patients. In clinical trials adverse events which occurred with quinapril were also seen with ACCURETIC. In addition, the following were reported for quinapril at an incidence >0.5%: depression, back pain, constipation, syncope, and amblyopia. Hydrochlorothiazide has been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency. 22 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda BODY AS A WHOLE: CARDIOVASCULAR: DIGESTIVE: NEUROLOGIC: MUSCULOSKELETAL: HEMATOLOGIC: RENAL: METABOLIC: HYPERSENSITIVITY: Weakness. Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics). Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia. Vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. Muscle spasm. Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and hemolytic anemia. Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS). Hyperglycemia, glycosuria, and hyperuricemia. Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Clinical Laboratory Test Findings Serum Electrolytes: See PRECAUTIONS. Creatinine, Blood Urea Nitrogen: Increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4%, respectively, of patients treated with ACCURETIC. Most increases were minor and reversible, which can occur in patients with essential hypertension but most frequently in patients with renal artery stenosis (see PRECAUTIONS). PBI and Tests of Parathyroid Function: See PRECAUTIONS. Hematology: See WARNINGS. Other (causal relationships unknown): Other clinically important changes in standard laboratory tests were rarely associated with ACCURETIC administration. Elevations in uric 23 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda acid, glucose, magnesium, cholesterol, triglyceride, and calcium (see PRECAUTIONS) have been reported. OVERDOSAGE No specific information is available on the treatment of overdosage with ACCURETIC or quinapril monotherapy; treatment should be symptomatic and supportive. Therapy with ACCURETIC should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures. The oral median lethal dose of quinapril/hydrochlorothiazide in combination ranges from 1063/664 to 4640/2896 mg/kg in mice and rats. Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats. In single-dose studies of hydrochlorothiazide, most rats survived doses up to 2.75 g/kg. Data from human overdoses of ACE inhibitors are scanty; the most likely manifestation of human quinapril overdosage is hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of quinapril and its metabolites. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of quinapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution. 24 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION As individual monotherapy, quinapril is an effective treatment of hypertension in once- daily doses of 10 to 80 mg and hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of quinapril/hydrochlorothiazide combination therapy using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing dose of either component. The side effects (see WARNINGS) of quinapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of quinapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens that combine low doses of hydrochlorothiazide with quinapril produce minimal effects on serum potassium. In clinical trials of ACCURETIC, the average change in serum potassium was near zero in subjects who received HCTZ 6.25 mg in the combination, and the average subject who received 10 to 40/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Therapy Guided by Clinical Effect Patients whose blood pressures are not adequately controlled with quinapril monotherapy may instead be given ACCURETIC 10/12.5 or 20/12.5. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve blood pressure control with less electrolyte disturbance if they are switched to ACCURETIC 10/12.5 or 20/12.5. 25 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Replacement Therapy For convenience, patients who are adequately treated with 20 mg of quinapril and 25 mg of hydrochlorothiazide and experience no significant electrolyte disturbances may instead wish to receive ACCURETIC 20/25. Use in Renal Impairment Regimens of therapy with ACCURETIC need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73 m2 (serum creatinine roughly 3 mg/dL or 265 mol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides. Therefore, ACCURETIC is not recommended for use in these patients. HOW SUPPLIED ACCURETIC is available in tablets of three different strengths: 10/12.5 tablets: pink, scored elliptical, biconvex, film-coated tablets coded “PD 222” on one side. Each tablet contains 10 mg of quinapril and 12.5 mg of hydrochlorothiazide. NDC 0071-0222-23: 90 tablet bottles 20/12.5 tablets: pink, scored triangular, film-coated tablets coded “PD 220” on one side. Each tablet contains 20 mg of quinapril and 12.5 mg of hydrochlorothiazide. NDC 0071-0220-23: 90 tablet bottles 20/25 tablets: pink, round, biconvex, film-coated tablets coded “PD 223” on one side. Each tablet contains 20 mg of quinapril and 25 mg of hydrochlorothiazide. NDC 0071-0223-23: 90 tablet bottles Dispense in tight containers as defined in the USP. Store at Controlled Room Temperature 20–25C (68–77F) [see USP]. 26 Reference ID: 3818285 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0216-16.x Revised September 2015 Reference ID: 3818285 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:47.806591	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020125s020lbl.pdf', 'application_number': 20125, 'submission_type': 'SUPPL ', 'submission_number': 20}
12,239	NDA 21-276 Final Labeling June 29, 2001 1 ESTROSTEP® (Norethindrone Acetate and Ethinyl Estradiol Tablets, USP) ESTROSTEP® 21 (Each white triangular tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol; each white square tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; each white round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol.) ESTROSTEP® Fe (Each white triangular tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol; each white square tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; each white round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol; each brown tablet contains 75 mg ferrous fumarate.) Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. DESCRIPTION ESTROSTEP is a graduated estrophasic providing estrogen in a graduated sequence over a 21-day period with a constant dose of progestogen. ESTROSTEP 21 provides for a 21-day dosage regimen of oral contraceptive tablets. ESTROSTEP Fe provides for a continuous dosage regimen consisting of 21 oral contraceptive tablets and seven ferrous fumarate tablets. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen, are non-hormonal, and do not serve any therapeutic purpose. Each white triangle-shaped tablet contains 1 mg norethindrone acetate [(17 alpha)- 17-(acetyloxy)-19-norpregna-4-en-20-yn-3-one] and 20 mcg ethinyl estradiol [(17 alpha)- 19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol]; each white square-shaped tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; and each white round tablet contains 1 mg norethindrone acetate, 35 mcg ethinyl estradiol. Each tablet also contains calcium stearate; lactose; microcrystalline cellulose; and starch. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 2 The structural formulas are as follows: Each brown tablet contains microcrystalline cellulose; ferrous fumarate; magnesium stearate; povidone; sodium starch glycolate; sucrose with modified dextrins. Each ESTROSTEP 21 tablet dispenser contains five white triangular tablets, seven white square tablets, and nine white round tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, followed by one square tablet each day for seven days, and then one round tablet each day for nine days. Each ESTROSTEP Fe tablet dispenser contains five white triangular tablets, seven white square tablets, nine white round tablets, and seven brown tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, then one square tablet each day for seven days, followed by one round tablet each day for nine days, and then one brown tablet each day for seven days. CLINICAL PHARMACOLOGY ORAL CONTRACEPTION Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). In vitro and animal studies have shown that norethindrone combines high progestational activity with low intrinsic androgenicity. In humans, norethindrone acetate in combination with ethinyl estradiol does not counteract estrogen-induced increases in sex hormone binding globulin (SHBG). Following multiple-dose administration of ESTROSTEP, serum SHBG concentrations increase two- to three-fold and free This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 3 testosterone concentrations decrease by 47% to 64%, indicating minimal androgenic activity. ACNE Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of norethindrone acetate and ethinyl estradiol increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. Pharmacokinetics Absorption Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol. Administration of norethindrone acetate/ethinyl estradiol with a high fat meal decreases rate, but not extent, of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration with food. Plasma concentrations of norethindrone and ethinyl estradiol following chronic administration of ESTROSTEP to 17 women are shown below (Figure 1). Mean steady- state concentrations of norethindrone for the 1/20, 1/30, and 1/35 tablet strengths increased as ethinyl estradiol dose increased over the 21-day dose regimen, due to dose- dependent effects of ethinyl estradiol on serum SHBG concentrations (Table 1). Mean steady-state plasma concentrations of ethinyl estradiol for the 1/20, 1/30, and 1/35 tablet strengths were proportional to ethinyl estradiol dose (Table 1). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 4 Time (hours) 0 6 12 18 24 Mean Plasma Ethinyl Estradiol Concentration (pg/mL) 0 20 40 60 80 100 120 1/20 1/30 1/35 Time (hours) 0 6 12 18 24 Mean Plasma Norethindrone Concentration (ng/mL) 0 2 4 6 8 10 12 1/20 1/30 1/35 Figure 1. Mean Steady-State Plasma Ethinyl Estradiol and Norethindrone Concentrations Following Chronic Administration of ESTROSTEP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 5 Table 1. Mean (SD) Steady-State Pharmacokinetic Parameters Following Chronic Administration of ESTROSTEPa Norethindrone Acetate/Ethinyl Estradiol Dose Cycle Day Cmax AUC CL/F SHBGb Norethindrone mg/µg ng/mL ng·hr/mL mL/min nmol/L 1/20 5 10.8 81.1 220 120 (3.9) (28.5) (137) (33) 1/30 12 12.7 102 166 139 (4.1) (32) (85) (42) 1/35 21 12.7 109 152 163 (4.1) (32) (73) (40) Ethinyl Estradiol mg/µg pg/mL pg·hr/mL mL/min nmol/L 1/20 5 61.0 661 549 (16.8) (190) (171) 1/30 12 92.4 973 546 (26.9) (293) (199) 1/35 21 113 1149 568 (44) (372) (219) a Cmax = Maximum plasma concentration; AUC(0-24) = Area under the plasma concentration-time curve over the dosing interval; CL/F = Apparent oral clearance. b Mean (SD) baseline value = 55 (29) nmol/L. No age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of ESTROSTEP to 119 postmenarchal women ages 15 to 48 years. Distribution Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. ESTROSTEP increases serum SHBG concentrations two- to three-fold (Table 1). Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 6 and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first- pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation. Excretion Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites . Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of ESTROSTEP are approximately 13 hours and 19 hours, respectively. Special Population Race The effect of race on the disposition of ESTROSTEP has not been evaluated. Renal Insufficiency The effect of renal disease on the disposition of ESTROSTEP has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function. Hepatic Insufficiency The effect of hepatic disease on the disposition of ESTROSTEP has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function. Drug-Drug Interactions Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions. INDICATIONS AND USAGE ESTROSTEP is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. ESTROSTEP is indicated for the treatment of moderate acne vulgaris in females, ≥15 years of age, who have no known contraindications to oral contraceptive therapy, desire oral contraception, have achieved menarche, and are unresponsive to topical anti- acne medications. ESTROSTEP should be used for the treatment of acne only if the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 7 patient desires an oral contraceptive for birth control and plans to stay on it for at least 6 months. Oral contraceptives are highly effective for pregnancy prevention. Table 2 lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 8 Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year3 Method (1) Typical Use 1 (2) Perfect Use2 (3) (4) Chance4 85 85 Spermicides5 26 6 40 Periodic Abstinence 25 63 Calendar 9 Ovulation Method 3 Symptothermal6 2 Post-ovulation 1 Cap7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm7 20 6 56 Withdrawal 19 4 Condom8 Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera 0.3 0.3 70 Norplant and Norplant-2 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 9 Emergency Contraceptives Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9 Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10 Source: Trussell J, The Essentials of Contraception. In Hatcher RA, Trussell J, Stewart F, Cates W, Stweart GK, Kowel D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. 1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for 1 year. 4 The percentages becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5 Foams, creams, gels, vaginal suppositories, and vaginal film. 6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7 With spermicidal cream or jelly. 8 Without spermicides. 9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 4 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills). 10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. ESTROSTEP was evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, Phase 3, six (28 day) cycle studies. A total of 295 patients received ESTROSTEP and 296 received placebo. Mean age at enrollment for both groups was 24 years. At six months each study demonstrated a statistically significant difference between ESTROSTEP and placebo for mean change from baseline in lesion counts (see Table 3 and Figure 2). Each study also demonstrated overall treatment success in the investigator’s global evaluation. Patients with severe androgen excess were not studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 10 Table 3. Acne Vulgaris Indication Pooled Data 376-403 and 376-404 Observed Means at Six Months and at Baseline* Intent To Treat Population ESTROSTEP N=296 Placebo N=295 Difference in Counts Between Estrostep and Placebo at Six Months (95% CI)** Number of Lesions Counts % reduction Counts % reduction INFLAMMATORY LESIONS Baseline Mean Sixth Month Mean 29 14 52% 29 17 41% 3 (±2 ) NON-INFLAMMATORY Baseline Mean Sixth Month Mean 44 27 38% 43 32 25% 5 (±3.5 ) TOTAL LESIONS Baseline Mean Sixth Month Mean 74 42 43% 72 49 32% 7 (±5) Numbers rounded to nearest integer Limits for 95% Confidence Interval; not adjusted for baseline differences ESTROSTEP users who started with about 74 acne lesions had about 42 lesions after 6 months of treatment. Placebo users who started with about 72 acne lesions had about 49 lesions after the same duration of treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 11 Mean Total Lesion Counts: Estrostep (N = 296) 74 62 56 52 48 46 42 Placebo (N = 295) 72 60 57 55 53 51 49 0 10 20 30 40 50 60 70 80 90 100 Baseline 1 2 3 4 5 6 Cycle Mean Percent Reduction Placebo Estrostep Intent-to-Treat Population Figure 2. Mean Percent Reduction in Total Lesion Counts From Baseline to Each 28-Day Cycle and Mean Total Lesion Counts at Each Cycle Following Administration of ESTROSTEP and Placebo (Statistically significant differences were not found in both studies individually until cycle 6) CONTRAINDICATIONS Oral contraceptives should not be used in women who currently have the following conditions: • Thrombophlebitis or thromboembolic disorders • A past history of deep vein thrombophlebitis or thromboembolic disorders • Cerebral vascular or coronary artery disease • Known or suspected carcinoma of the breast • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia • Undiagnosed abnormal genital bleeding This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 12 • Cholestatic jaundice of pregnancy or jaundice with prior pill use • Hepatic adenomas or carcinomas • Known or suspected pregnancy WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from References 8 and 9 with the author's permission). For further information, the reader is referred to a text on epidemiological methods. 1. Thromboembolic Disorders and Other Vascular Problems a. Myocardial infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 13 diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Figure3) among women who use oral contraceptives. Figure 3 Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see Section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 14 predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped. A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than 4 to 6 weeks after delivery in women who elect not to breast feed. c. Cerebrovascular disease Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years) hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension . The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension . The attributable risk is also greater in older women. d. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives. The amount and activity of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 15 e. Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever- users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens. 2. Estimates of Mortality From Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 4). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s but not reported until 1983 . However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling. Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1-4; and Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 16 Table 4 Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility Per 100,000 Nonsterile Women by Fertility Control Method According to Age Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility control methods 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth related. ** Deaths are method related. Adapted from H.W. Ory, Reference 41. 3. Carcinoma of the Reproductive Organs and Breasts Epidemiologic studies have been conducted examining the relationship between combination oral contraceptives and breast cancer. ESTROSTEP was not included in these studies, and the majority of the combination oral contraceptives used by women in these studies have higher doses of estrogen than ESTROSTEP. These studies suggest that the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives; however, these studies do not provide evidence for causation. The observed pattern of increased risk of breast cancer diagnosis may be due to earlier detection of breast cancer in combination oral contraceptive users, the biological effects of combination oral contraceptives, or a combination of reasons. The risk appears to decrease over time after combination oral contraceptive discontinuation, and by 10 years after cessation of combination oral contraceptive use, the additional risk disappears. The risk does not appear to increase with duration of use and no consistent relationships have been found with age at first use or doses studied or type of steroid. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman’s reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous combination oral contraceptive users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormonally-sensitive tumor. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 17 4. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after 4 or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the US, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. Oral Contraceptive Use Before and During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 7. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 18 8. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance . Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 9. Elevated Blood Pressure An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use . Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases or renal disease should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever and never users. 10. Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. 11. Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered, and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of prolonged breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 19 PRECAUTIONS 1. Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 2. Physical Examination and Follow-Up It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. Lipid Disorders Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. Liver Function If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. Emotional Disorders Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 7. Contact Lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 20 8. Drug Interactions Effects of Other Drugs on Oral Contraceptives Rifampin: Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a reduction in contraceptive effectiveness. Antibiotics: Pregnancy while taking oral contraceptives has been reported when the oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids. Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. St. John’s Wort: Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of oral contraceptives. This may also result in breakthrough bleeding. Other: Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone. Effects of Oral Contraceptives on Other Drugs Oral contraceptive combinations containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives. 9. Interactions with Laboratory Tests Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 21 a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 10. Carcinogenesis See WARNINGS section. 11. Pregnancy Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections. 12. Nursing Mothers Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. 13. Pediatric Use Safety and efficacy of ESTROSTEP have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 14. Geriatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 22 This product has not been studied in women over 65 years of age and is not indicated in this population. INFORMATION FOR THE PATIENT See patient labeling printed below. ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section): • Thrombophlebitis • Arterial thromboembolism • Pulmonary embolism • Myocardial infarction • Cerebral hemorrhage • Cerebral thrombosis • Hypertension • Gallbladder disease • Hepatic adenomas or benign liver tumors There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed: • Mesenteric thrombosis • Retinal thrombosis The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: • Nausea • Vomiting • Gastrointestinal symptoms (such as abdominal cramps and bloating) • Breakthrough bleeding • Spotting • Change in menstrual flow • Amenorrhea • Temporary infertility after discontinuation of treatment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 23 • Edema • Melasma which may persist • Breast changes: tenderness, enlargement, secretion • Change in weight (increase or decrease) • Change in cervical erosion and secretion • Diminution in lactation when given immediately postpartum • Cholestatic jaundice • Migraine • Rash (allergic) • Mental depression • Reduced tolerance to carbohydrates • Vaginal candidiasis • Change in corneal curvature (steepening) • Intolerance to contact lenses The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted: • Pre-menstrual syndrome • Cataracts • Changes in appetite • Cystitis-like syndrome • Headache • Nervousness • Dizziness • Hirsutism • Loss of scalp hair • Erythema multiforme • Erythema nodosum • Hemorrhagic eruption • Vaginitis • Porphyria • Impaired renal function This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 24 • Hemolytic uremic syndrome • Budd-Chiari syndrome • Acne • Changes in libido • Colitis OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol. Effects on menses: • Increased menstrual cycle regularity • Decreased blood loss and decreased incidence of iron deficiency anemia • Decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: • Decreased incidence of functional ovarian cysts • Decreased incidence of ectopic pregnancies Effects from long-term use: • Decreased incidence of fibroadenomas and fibrocystic disease of the breast • Decreased incidence of acute pelvic inflammatory disease • Decreased incidence of endometrial cancer • Decreased incidence of ovarian cancer DOSAGE AND ADMINISTRATION The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in either three or four rows of seven This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 25 tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets. Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen. Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days. Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday- Start regimen. The possibility of ovulation and conception prior to initiation of use should be considered. Dosage and Administration for 21-Day Dosage Regimen To achieve maximum contraceptive effectiveness, ESTROSTEP 21 must be taken exactly as directed and at intervals not exceeding 24 hours. ESTROSTEP 21 provides the patient with a convenient tablet schedule of “3 week off." Two dosage regimens are described, one of which may be more convenient or suitable than the other for an individual patient. For the initial cycle of therapy, the patient begins her tablets according to the Day-1 Start or Sunday-Start regimen. With either regimen, the patient takes one tablet daily for 21 consecutive days followed by one week of no tablets. A. Sunday-Start Regimen: The patient begins taking tablets from the top row on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first tablet is taken on the same day. The last tablet in the dispenser will then be taken on a Saturday, followed by no tablets for a week (7 days). For all subsequent cycles, the patient then begins a new 21-tablet regimen on the eighth day, Sunday, after taking her last tablet. Following this regimen of 21 days on—7 days off, the patient will start all subsequent cycles on a Sunday. B. Day-1 Start Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one tablet daily, beginning with the first tablet in the top row. The patient completes her 21-tablet regimen when she has taken the last tablet in the tablet dispenser. She will then take no tablets for a week (7 days). For all subsequent cycles, the patient begins a new 21-tablet regimen on the eighth day after taking her last tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 days on—7 days off, the patient will start all subsequent cycles on the same day of the week as the first course. Likewise, the interval of no tablets will always start on the same day of the week. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 26 Tablets should be taken regularly at the same time each day and can be taken without regard to meals. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule. Special Notes on Administration Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after discontinuing medication. If spotting occurs while on the usual regimen of one tablet daily, the patient should continue medication without interruption. If a patient forgets to take one or more white tablets, the following is suggested: One tablet is missed • take tablet as soon as remembered • take next tablet at the regular time Two consecutive tablets are missed (Week 1 or Week 2) • take two tablets as soon as remembered • take two tablets the next day • use another birth control method for seven days following the missed tablets Two consecutive tablets are missed (Week 3) Sunday-Start Regimen: • take one tablet daily until Sunday • discard remaining tablets • start new pack of tablets immediately (Sunday) • use another birth control method for seven days following the missed tablets Day-1 Start Regimen: • discard remaining tablets • start new pack of tablets that same day • use another birth control method for seven days following the missed tablets Three (or more) consecutive tablets are missed Sunday-Start Regimen: • take one tablet daily until Sunday • discard remaining tablets This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 27 • start new pack of tablets immediately (Sunday) • use another birth control method for seven days following the missed tablets Day-1 Start Regimen: • discard remaining tablets • start new pack of tablets that same day • use another birth control method for seven days following the missed tablets The possibility of ovulation occurring increases with each successive day that scheduled tablets are missed. While there is little likelihood of ovulation occurring if only one tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive tablets are missed. In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day 1) depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered. Dosage and Administration for 28-Day Dosage Regimen To achieve maximum contraceptive effectiveness, ESTROSTEP Fe should be taken exactly as directed and at intervals not exceeding 24 hours. ESTROSTEP Fe provides a continuous administration regimen consisting of 21 white tablets of ESTROSTEP and seven brown non-hormone containing tablets of ferrous fumarate. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen and do not serve any therapeutic purpose. There is no need for the patient to count days between cycles because there are no “off-tablet days.” A. Sunday-Start Regimen: The patient begins taking the first white tablet from the top row of the dispenser (labeled Sunday) on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first white tablet is taken on the same day. The patient takes one white tablet daily for 21 days. The last white tablet in the dispenser will be taken on a Saturday. Upon completion of all 21 white tablets, and without interruption, the patient takes one brown tablet daily for 7 days. Upon completion of this first course of tablets, the patient begins a second course of 28-day tablets, without interruption, the next day (Sunday), starting with the Sunday white tablet in the top row. Adhering to this regimen of one white tablet daily for 21 days, followed without interruption by one brown tablet daily for 7 days, the patient will start all subsequent cycles on a Sunday. B. Day-1 Start Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one white tablet daily, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 28 beginning with the first white tablet in the top row. After the last white tablet (at the end of the third row) has been taken, the patient will then take the brown tablets for a week (7 days). For all subsequent cycles, the patient begins a new 28 tablet regimen on the eighth day after taking her last white tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 white tablets and 7 brown tablets, the patient will start all subsequent cycles on the same day of the week as the first course. Tablets should be taken regularly at the same time each day and can be taken without regard to meals. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule. Special Notes on Administration Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after the brown tablets have been started. In any event, the next course of tablets should be started without interruption. If spotting occurs while the patient is taking white tablets, continue medication without interruption. If the patient forgets to take one or more white tablets, the following is suggested: One tablet is missed • take tablet as soon as remembered • take next tablet at the regular time Two consecutive tablets are missed (Week 1 or Week 2) • take two tablets as soon as remembered • take two tablets the next day • use another birth control method for seven days following the missed tablets Two consecutive tablets are missed (Week 3) Sunday-Start Regimen: • take one tablet daily until Sunday • discard remaining tablets • start new pack of tablets immediately (Sunday) • use another birth control method for seven days following the missed tablets Day-1 Start Regimen: • discard remaining tablets This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 29 • start new pack of tablets that same day • use another birth control method for seven days following the missed tablets Three (or more) consecutive tablets are missed Sunday-Start Regimen: • take one tablet daily until Sunday • discard remaining tablets • start new pack of tablets immediately (Sunday) • use another birth control method for seven days following the missed tablets Day-1 Start Regimen: • discard remaining tablets • start new pack of tablets that same day • use another birth control method for seven days following the missed tablets The possibility of ovulation occurring increases with each successive day that scheduled white tablets are missed. While there is little likelihood of ovulation occurring if only one white tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive white tablets are missed. If the patient forgets to take any of the seven brown tablets in week four, those brown tablets that were missed are discarded and one brown tablet is taken each day until the pack is empty. A back-up birth control method is not required during this time. A new pack of tablets should be started no later than the eighth day after the last white tablet was taken. In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day-1) depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered. Use of Oral Contraceptives in the Event of a Missed Menstrual Period 1. If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 30 After several months on treatment, bleeding may be reduced to a point of virtual absence. This reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy. Acne The timing of initiation of dosing with ESTROSTEP for acne should follow the guidelines for use of ESTROSTEP as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section for oral contraceptives. HOW SUPPLIED ESTROSTEP 21 is available in dispensers each containing 21 white tablets. The first five triangle tablets each contain 1 mg of norethindrone acetate and 20 mcg of ethinyl estradiol; the next seven square tablets each contain 1 mg of norethindrone acetate and 30 mcg of ethinyl estradiol; the last nine round tablets each contain 1 mg of norethindrone acetate and 35 mcg of ethinyl estradiol. Available in packages of five dispensers. ESTROSTEP Fe is available in dispensers each containing 21 white tablets. The first five triangle tablets each contain 1 mg of norethindrone acetate and 20 mcg of ethinyl estradiol; the next seven square tablets each contain 1 mg of norethindrone acetate and 30 mcg of ethinyl estradiol; the next nine round tablets each contain 1 mg of norethindrone acetate and 35 mcg of ethinyl estradiol; and the last seven (brown) tablets each contain 75 mg ferrous fumarate. Available in packages of five dispensers. Storage—Do not store above 25°°C (77°°F). Protect from light. Store tablets inside pouch when not in use. REFERENCES AVAILABLE UPON REQUEST. BRIEF SUMMARY PATIENT PACKAGE INSERT ESTROSTEP (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases. Oral contraceptives, also known as “birth control pills” or “the pill pregnancy and, when taken correctly, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 31 ESTROSTEP may also be taken to treat moderate acne in females who are at least 15 years of age, have started having menstrual periods, are able to use the pill and want the pill for birth control, plan to stay on the pill for at least 6 months, and have not improved with acne medicines that are put on the skin. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life- threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: • Smoke • Have high blood pressure, diabetes, high cholesterol • Have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Most side effects of the pill are not serious. The most common side effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea, vomiting, and breakthrough bleeding, may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris), or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 32 The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or health care provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease oral contraceptive effectiveness. Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the increase in breast cancer diagnoses is caused by the pill. You should have regular breast examinations by a health care provider and examine your own breasts monthly. Tell your health care provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor. Some studies have found an increase in the incidence of precancerous lesions of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. Taking the pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your health care provider. Your health care provider will take a medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your health care provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your health care provider. ESTROSTEP (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. INSTRUCTIONS TO PATIENT TABLET DISPENSER The ESTROSTEP tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in either three or four rows of seven tablets each with the days of the week appearing above the first row of tablets. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 33 If your TABLET DISPENSER contains: You are taking: 21 white tablets ESTROSTEP 21 21 white tablets and 7 brown tablets ESTROSTEP Fe Each triangle tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. Each square tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol. Each round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol. Each brown tablet contains 75 mg ferrous fumarate and is intended to help you remember to take the tablets correctly. These brown tablets are not intended to have any health benefit. DIRECTIONS To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your doctor or clinic. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 34 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or spermicide) until you check with your doctor or clinic. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS: The 21-pill pack has 21 “active” white pills (with hormones) to take for 3 weeks, followed by 1 week without pills. The 28-pill pack has 21 “active” white pills (with hormones) to take for 3 weeks, followed by 1 week of reminder brown pills (without hormones). 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills (follow the arrows), and 3) the week numbers as shown in the following pictures: Each ESTROSTEP 21 tablet dispenser contains five white triangular tablets, seven white square tablets, and nine white round tablets. These tablets are to be taken in the following This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 35 order: one triangular tablet each day for five days, followed by one square tablet each day for seven days, and then one round tablet each day for nine days. ESTROSTEP 21 will contain: ALL WHITE PILLS Each ESTROSTEP Fe tablet dispenser contains five white triangular tablets, seven white square tablets, nine white round tablets, and seven brown tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, then one square tablet each day for seven days, followed by one round tablet each day for nine days, and then one brown tablet each day for seven days. ESTROSTEP Fe will contain: 21 WHITE PILLS for Weeks 1, 2, and 3. Week 4 will contain BROWN PILLS ONLY. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember. DAY-1 START: 1. Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 36 2. Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. 3. Take the first "active" white pill of the first pack during the first 24 hours of your period. 4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first “active” white pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or spermicide are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: 21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs. 28 pills: Start the next pack on the day after your last “reminder” pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 white “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white “active” pills in a row in Week 1 OR Week 2 of your pack: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 37 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white “active” pill every day for 7 days. If you MISS 2 white “active” pills in a row in THE 3rd WEEK: If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 2. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white “active” pill every day for 7 days. If you MISS 3 OR MORE white “active” pills in a row (during the first 3 weeks): If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 2. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white “active” pill every day for 7 days. A REMINDER FOR THOSE ON 28-DAY PACKS: IF YOU FORGET ANY OF THE 7 BROWN “REMINDER” PILLS IN Week 4: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 38 THROW AWAY THE PILLS YOU MISSED. KEEP TAKING 1 PILL EACH DAY UNTIL THE PACK IS EMPTY. YOU DO NOT NEED A BACK-UP METHOD. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE WHITE “ACTIVE” PILL EACH DAY until you can reach your doctor or clinic. Based on his or her assessment of your medical needs, your doctor or health care provider has prescribed this drug for you. Do not give this drug to anyone else. Keep this and all drugs out of the reach of children. Rx only Storage—Do not store above 25°C (77°F). Protect from light. Store tablets inside pouch when not in use. DETAILED PATIENT PACKAGE INSERT ESTROSTEP (like all oral contraceptives) are intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases. What You Should Know About Oral Contraceptives Any woman who considers using oral contraceptives (the “birth control pill” or “the pill”) should understand the benefits and risks of using this form of birth control. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your health care provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your health care provider’s advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or “birth control pills’’ or “the pill’’ are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. When they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. Typical failure rates are actually 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 39 In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: Implant: <1% Male sterilization: <1% Injection: <1% Cervical Cap: 20 to 40% IUD: <1 to 2% Condom alone (male): 14% Diaphragm with spermicides: 20% Condom alone (female): 21% Spermicides alone: 26% Periodic abstinence: 25% Vaginal Sponge: 20 to 40% Withdrawal: 19% Female sterilization: <1% No method: 85% ESTROSTEP may also be taken to treat moderate acne if all of the following are true: • Your doctor says it is safe for you to use the pill • You are at least 15 years old • You have started having menstrual periods • You want to use the pill for birth control • You plan to stay on the pill for at least 6 months • Your acne has not improved with acne medicines that you put on your skin. ESTROSTEP users who started with about 74 acne pimples had about 42 pimples after 6 months of treatment. Placebo users who started with about 72 acne pimples had about 49 pimples after six months of treatment. Use ESTROSTEP to treat acne only if you want the pill for birth control and plan to stay on it for at least 6 months. WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Some women should not use the pill. For example, you should not take the pill if you are pregnant or think you may be pregnant. You should also not use the pill if you have any of the following conditions: • A history of heart attack or stroke • Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes • A history of blood clots in the deep veins of your legs • Chest pain (angina pectoris) • Known or suspected breast cancer or cancer of the lining of the uterus, cervix, or vagina This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 40 • Unexplained vaginal bleeding (until a diagnosis is reached by your doctor) • Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill • Liver tumor (benign or cancerous) • Known or suspected pregnancy Tell your health care provider if you have ever had any of these conditions. Your health care provider can recommend a safer method of birth control. OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your health care provider if you have: • Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram • Diabetes • Elevated cholesterol or triglycerides • High blood pressure • Migraine or other headaches or epilepsy • Mental depression • Gallbladder, heart, or kidney disease • History of scanty or irregular menstrual periods Women with any of these conditions should be checked often by their health care provider if they choose to use oral contraceptives. Also, be sure to inform your doctor or health care provider if you smoke or are on any medications. RISKS OF TAKING ORAL CONTRACEPTIVES 1. Risk of Developing Blood Clots Blood clots and blockage of blood vessels are the most serious side effects of taking oral contraceptives; in particular, a clot in the leg can cause thrombophlebitis, and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness, or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your doctor about stopping oral contraceptives three to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 41 four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breast feeding. If you are breast feeding, you should wait until you have weaned your child before using the pill. (See also the section on Breast Feeding in GENERAL PRECAUTIONS.) 2. Heart Attacks and Strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder Disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver Tumors In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, a possible but not definite association has been found with the pill and liver cancers in two studies, in which a few women who developed these very rare cancers were found to have used oral contraceptives for long periods. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 5. Cancer of the Reproductive Organs and Breasts Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the increase in breast cancer diagnosis is caused by the pill. You should have regular breast examinations by a health care provider and examine your own breasts monthly. Tell your health care provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor. Some studies have found an increase in the incidence of precancerous lesions of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 42 ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility Per 100,000 Nonsterile Women by Fertility Control Method According to Age Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility control methods* Oral contraceptives non-smoker Oral contraceptives smoker IUD** Condom* Diaphragm/spermicide* Periodic abstinence* 7.0 0.3 2.2 0.8 1.1 1.9 2.5 7.4 0.5 3.4 0.8 1.6 1.2 1.6 9.1 0.9 6.6 1.0 0.7 1.2 1.6 14.8 1.9 13.5 1.0 0.2 1.3 1.7 25.7 13.8 51.1 1.4 0.3 2.2 2.9 28.2 31.6 117.2 1.4 0.4 2.8 3.6 * Deaths are birth related. ** Deaths are method related. In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who don’t smoke should not take oral contraceptives is based on information from older higher dose pills and on less selective use of pills than is practiced today. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. However, all women, especially older women, are cautioned to use the lowest dose pill that is effective. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 43 WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your doctor immediately: • Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) • Pain in the calf (indicating a possible clot in the leg) • Crushing chest pain or heaviness in the chest (indicating a possible heart attack) • Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) • Sudden partial or complete loss of vision (indicating a possible clot in the eye) • Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or health care provider to show you how to examine your breasts) • Severe pain or tenderness in the stomach area (indicating a possible ruptured liver tumor) • Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) • Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) SIDE EFFECTS OF ORAL CONTRACEPTIVES 1. Vaginal Bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your doctor or health care provider. 2. Contact Lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your doctor or health care provider. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 44 3. Fluid Retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your doctor or health care provider. 4. Melasma A spotty darkening of the skin is possible, particularly of the face. 5. Other Side Effects Other side effects may include change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, and vaginal infections. If any of these side effects bother you, call your doctor or health care provider. GENERAL PRECAUTIONS 1. Missed Periods and Use of Oral Contraceptives Before or During Early Pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your health care provider before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your health care provider immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these studies have not been confirmed. Nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly necessary and prescribed by your doctor. You should check with your doctor about risks to your unborn child of any medication taken during pregnancy. 2. While Breast Feeding If you are breast feeding, consult your doctor before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breast feeding. You should use another method of contraception since breast feeding provides only partial protection from becoming pregnant, and this partial protection decreases significantly as you breast feed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 45 for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely. 3. Laboratory Tests If you are scheduled for any laboratory tests, tell your doctor you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug Interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin; drugs used for epilepsy such as barbiturates (for example, phenobarbital), carbamazepine, and phenytoin (Dilantin® is one brand of this drug); phenylbutazone; and possibly St. John’s Wort and certain antibiotics. You may need to use additional contraception when you take drugs which can make oral contraceptives less effective. Birth control pills interact with certain drugs. These drugs include acetaminophen, clofibric acid, cyclosporine, morphine, prednisolone, salicylic acid, temazepam, and theophylline. You should tell your doctor if you are taking any of these medications. 5. Sexually Transmitted Diseases ESTROSTEP (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. INSTRUCTIONS TO PATIENT TABLET DISPENSER The ESTROSTEP tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in either three or four rows of seven tablets each with the days of the week appearing above the first row of tablets. If your TABLET DISPENSER contains: You are taking: 21 white tablets ESTROSTEP 21 21 white tablets and 7 brown tablets ESTROSTEP Fe Each triangle tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. Each square tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 46 Each round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol. Each brown tablet contains 75 mg ferrous fumarate and is intended to help you remember to take the tablets correctly. These brown tablets are not intended to have any health benefit. DIRECTIONS To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your doctor or clinic. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or spermicide) until you check with your doctor or clinic. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 47 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS: The 21-pill pack has 21 “active” white pills (with hormones) to take for 3 weeks, followed by 1 week without pills. The 28-pill pack has 21 “active” white pills (with hormones) to take for 3 weeks, followed by 1 week of reminder brown pills (without hormones). 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills (follow the arrows), and 3) the week numbers as shown in the following pictures: Each ESTROSTEP 21 tablet dispenser contains five white triangular tablets, seven white square tablets, and nine white round tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, followed by one square tablet each day for seven days, and then one round tablet each day for nine days. ESTROSTEP 21 will contain: ALL WHITE PILLS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 48 Each ESTROSTEP Fe tablet dispenser contains five white triangular tablets, seven white square tablets, nine white round tablets, and seven brown tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, then one square tablet each day for seven days, followed by one round tablet each day for nine days, and then one brown tablet each day for seven days. ESTROSTEP Fe will contain: 21 WHITE PILLS for Weeks 1, 2, and 3. Week 4 will contain BROWN PILLS ONLY. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember. DAY-1 START: 1. Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) 2. Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. 3. Take the first “active” white pill of the first pack during the first 24 hours of your period. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 49 4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first “active” white pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or spermicide are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: 21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs. 28 pills: Start the next pack on the day after your last “reminder” pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 white “active” pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white “active” pills in a row in Week 1 OR Week 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 50 back-up method of birth control until you have taken a white “active” pill every day for 7 days. If you MISS 2 white “active” pills in a row in THE 3rd WEEK: 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white “active” pill every day for 7 days. If you MISS 3 OR MORE white “active” pills in a row (during the first 3 weeks): 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. 3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white “active” pill every day for 7 days. A REMINDER FOR THOSE ON 28-DAY PACKS: IF YOU FORGET ANY OF THE 7 BROWN “REMINDER” PILLS IN Week 4: THROW AWAY THE PILLS YOU MISSED. KEEP TAKING 1 PILL EACH DAY UNTIL THE PACK IS EMPTY. YOU DO NOT NEED A BACK-UP METHOD. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 51 FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE WHITE “ACTIVE” PILL EACH DAY until you can reach your doctor or clinic. PREGNANCY DUE TO PILL FAILURE The incidence of pill failure resulting in pregnancy is approximately 1% (ie, one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are about 5%. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your health care provider or pharmacist. OTHER INFORMATION Your health care provider will take a medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your health care provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your health care provider if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your health care provider, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 52 HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of oral contraceptives may provide certain benefits. They are: • Menstrual cycles may become more regular. • Blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur. • Pain or other symptoms during menstruation may be encountered less frequently. • Ectopic (tubal) pregnancy may occur less frequently. • Noncancerous cysts or lumps in the breast may occur less frequently. • Acute pelvic inflammatory disease may occur less frequently. • Oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your doctor or pharmacist. They have a more technical leaflet called the “Physician Insert,” which you may wish to read. Remembering to take tablets according to schedule is stressed because of its importance in providing you the greatest degree of protection. MISSED MENSTRUAL PERIODS FOR BOTH DOSAGE REGIMENS At times there may be no menstrual period after a cycle of pills. Therefore, if you miss one menstrual period but have taken the pills exactly as you were supposed to, continue as usual into the next cycle. If you have not taken the pills correctly and miss a menstrual period, you may be pregnant and should stop taking oral contraceptives until your doctor or health care provider determines whether or not you are pregnant. Until you can get to your doctor or health care provider, use another form of contraception. If two consecutive menstrual periods are missed, you should stop taking pills until it is determined whether or not you are pregnant. Although there does not appear to be any increase in birth defects in newborn babies, if you become pregnant while using oral contraceptives, you should discuss the situation with your doctor or health care provider. Periodic Examination Your doctor or health care provider will take a complete medical and family history before prescribing oral contraceptives. At that time and about once a year thereafter, he or she will generally examine your blood pressure, breasts, abdomen, and pelvic organs (including a Papanicolaou smear, ie, test for cancer). Keep this and all drugs out of the reach of children. Rx only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 21-276 Final Labeling June 29, 2001 53 Storage: Do not store above 25°C (77°F). Protect from light. Store tablets inside pouch when not in use. Revised June 2001 PARKE-DAVIS Div of Warner-Lambert Co ©1997-1999 Morris Plains, NJ 07950 USA Direct Medical Inquiries to: Parke-Davis Warner-Lambert Company 201 Tabor Road, Morris Plains, NJ 07950 Attn: Medical Affairs Department 0928G254 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28-DAY REGIMEN 28-DAY REGIMEN 28-DAY REGIMEN N 0071-0928-47 N 0071-0928-47 % only (norethindrone acetate and ethinyl estradiol tablets, USP and ferrous fumarate tablets) (norethindrone acetate and ethinyl estradiol tablets, USP and ferrous fumarate tablets) (norethindrone acetate and ethinyl estradiol tablets, USP and ferrous fumarate tablets) FIVE 28-TABLET DISPENSERS 28-DAY REGIMEN N 0071-0928-47 (norethindrone acetate and ethinyl estradiol tablets, USP and ferrous fumarate tablets) FIVE 28-TABLET DISPENSERS N 0071-0928-47 (norethindrone acetate and ethinyl estradiol tablets, USP and ferrous fumarate tablets) FIVE 28-TABLET DISPENSERS 0928C123 % only Each white, triangle-shaped tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol; each white, square-shaped tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; each white, round-shaped tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol; each brown tablet contains 75 mg ferrous fumarate. Usual Dosage: One tablet daily for 28 days as directed by the physician. See package insert for full prescribing information. Keep this and all drugs out of the reach of children. Do not store above 25˚ C (77˚ F). Protect from light. Store tablets in pouch when not in use. See end panel for expiration date and lot number. Ferrous fumarate tablets are not USP for dissolution and assay. FIVE 28-TABLET DISPENSERS FIVE 28-TABLET DISPENSERS © 1996-’00, Warner-Lambert Co. PARKE-DAVIS Div of Warner-Lambert Co/Morris Plains, NJ 07950 USA PHARMACIST: The "Brief Summary Patient Package Insert" enclosed in each unit is intended for the patient and should remain in the unit when dispensed. In addition, a copy of the "Detailed Patient Package Insert" should be given to the patient. 3 N x 0071-0928-47 *Ferrous fumarate tablets are not USP for dissolution and assay. 0928C123 0928C123 FPO FPO PHARMACIST: The "Brief Summary Patient Package Insert" enclosed in each unit is intended for the patient and should remain in the unit when dispensed. In addition, a copy of the "Detailed Patient Package Insert" should be given to the patient. FPO NOW with Sunday or Day-1 Start NOW with Sunday or Day-1 Start NOW with Sunday or Day-1 Start REDUCED - 70% CI-376 Estrostep Acne 115 NDA 21-276 Item 2 Vol 002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SUN START 0928E082 MON TUE WED THU FRI SAT PARKE-DAVIS Package/Graphic Design Morris Plains, NJ 07950 DESIGNER PROOFREADER 1 PROOFREADER 2 REGULATORY GRAPHICS MGR. PRODUCT MGR. 0928E083 – Estrostep Fe Blister Card PD Backup Disk 7 –Parke-Davis – Blisters Form 1/ Proof 1 / 2-3-97 / Sub (Norethindrone Acetate and Ethinyl Estradiol Tablets, USP and Ferrous Fumarate Tablets [not USP]) CI-376 Estrostep Acne 116 NDA 21-276 Item 2 Vol 002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.089623	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20130s7lbl.pdf', 'application_number': 20130, 'submission_type': 'SUPPL ', 'submission_number': 7}
12,238	ZONALON® (doxepin hydrochloride) CREAM, 5% FOR TOPICAL DERMATOLOGIC USE ONLY - NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. DESCRIPTION Zonalon (doxepin hydrochloride) Cream, 5% is a topical cream. Each gram contains: 50 mg of doxepin hydrochloride (equivalent to 44.3 mg of doxepin). Doxepin hydrochloride is one of a class of agents known as dibenzoxepin tricyclic antidepressant compounds. It is an isomeric mixture of N,N-dimethyldibenz[b,e]oxepin- ∆11(6H),γ- propylaminehydrochloride. Doxepin hydrochloride has an empirical formula of C19H21NO•HCl and a molecular weight of 316. INSERT THE STRUCTURAL FORMULA Zonalon Cream also contains sorbitol, cetyl alcohol, isopropyl myristate, glyceryl stearate, PEG-100 stearate, petrolatum, benzyl alcohol, titanium dioxide and purified water. CLINICAL PHARMACOLOGY Although doxepin HCl does have H1 and H2 histamine receptor blocking actions, the exact mechanism by which doxepin exerts its antipruritic effect is unknown. Zonalon Cream can produce drowsiness in significant numbers of patients, and this sedation may reduce awareness, including awareness of pruritic symptoms. In 19 pruritic eczema patients treated with Zonalon Cream, plasma doxepin concentrations ranged from nondetectable to 47 ng/mL from percutaneous absorption. Plasma levels from topical application of Zonalon Cream can result in CNS and other systemic side effects. Once absorbed into the systemic circulation, doxepin undergoes hepatic metabolism that results in conversion to pharmacologically-active desmethyldoxepin. Further glucuronidation results in urinary excretion of the parent drug and its metabolites. Desmethyldoxepin has a half-life that ranges from 28 to 52 hours and is not affected by multiple dosing. Plasma levels of both doxepin and desmethyldoxepin are highly variable and are poorly correlated with dosage. Wide distribution occurs in body tissues including lungs, heart, brain, and liver. Renal disease, genetic factors, age, and other medications affect the metabolism and subsequent elimination of doxepin. (See Precautions - Drug Interactions.) INDICATIONS AND USAGE Zonalon Cream is indicated for the short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus. (See Dosage and Administration.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS Because doxepin HCl has an anticholinergic effect and because significant plasma levels of doxepin are detectable after topical Zonalon Cream application, the use of Zonalon Cream is contraindicated in patients with untreated narrow angle glaucoma or a tendency to urinary retention. Zonalon Cream is contraindicated in individuals who have shown previous sensitivity to any of its components. WARNINGS Drowsiness occurs in over 20% of patients treated with Zonalon Cream, especially in patients receiving treatment to greater than 10% of their body surface area. Patients should be warned about the possibility of sedation and cautioned against driving a motor vehicle or operating hazardous machinery while being treated with Zonalon Cream. The sedating effects of alcoholic beverages, antihistamines, and other CNS depressants may be potentiated when Zonalon Cream is used. If excessive drowsiness occurs it may be necessary to reduce the frequency of applications, the amount of cream applied, and/or the percentage of body surface area treated, or discontinue the drug. However, the efficacy with reduced frequency of applications has not been established. Keep this product away from the eyes. PRECAUTIONS General Drowsiness: Since drowsiness may occur with the use of Zonalon Cream, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while using this drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on Zonalon Cream. (See PRECAUTIONS -- Geriatric Use .) Use under occlusion: Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings should not be utilized with Zonalon Cream. Contact sensitization: Use of Zonalon Cream can cause Type IV hypersensitivity reactions (contact sensitization) to doxepin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DRUG INTERACTIONS Studies have not been performed examining drug interactions with Zonalon Cream. However, since plasma levels of doxepin following topical application of Zonalon Cream can reach levels obtained with oral doxepin HCl therapy, the following drug interactions are possible following topical Zonalon Cream application: Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7- 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dosage regimen of a TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. MAO Inhibitors: Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with Zonalon Cream. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cimetidine: Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. Alcohol: Alcohol ingestion may exacerbate the potential sedative effects of Zonalon Cream. This is especially important in patients who may use alcohol excessively. Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of oral doxepin (75 mg/day). Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, mutagenesis, and impairment of fertility studies have not been conducted with doxepin hydrochloride. Pregnancy Category B: Reproduction studies have been performed in which doxepin was orally administered to rats and rabbits at doses up to 0.6 and 1.2 times, respectively, the estimated exposure to doxepin that results from use of 16 grams of Zonalon Cream per day (four applications of four grams of cream per day; dose multiples reflect comparisons made following normalization of the data on the basis of body surface area estimates) and have revealed no evidence of harm to rat or rabbit fetuses due to doxepin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. NURSING MOTHERS Doxepin is excreted in human milk after oral administration. It is possible that doxepin may also be excreted in human milk following topical application of Zonalon Cream. One case has been reported of apnea and drowsiness in a nursing infant whose mother was taking an oral dosage form of doxepin HCl. Because of the potential for serious adverse reactions in nursing infants from doxepin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. PEDIATRIC USE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The use of Zonalon Cream in pediatric patients is not recommended. Safe conditions for use of Zonalon Cream in children have not been established. One case has been reported of a 2.5 year old child who developed somnolence, grand mal seizure, respiratory depression, ECG abnormalities, and coma after treatment with Zonalon Cream. A total of 27 grams had been applied over three days for eczema. He was treated with supportive care, activated charcoal, and systemic alkalization and recovered. Geriatric Use: Clinical studies of Zonalon Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on Zonalon Cream. (See WARNINGS.) An 80-year old male nursing home patient developed probable systemic anticholinergic toxicity which included urinary retention and delirium after Zonalon cream had been applied to his arms, legs and back three times daily for two days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Controlled Clinical Trials Systemic Adverse Effects:In controlled clinical trials of patients treated with Zonalon Cream, the most common systemic adverse event reported was drowsiness. Drowsiness occurred in 71 of 330 (22%) of patients treated with Zonalon Cream compared to 7 of 334 (2%) of patients treated with vehicle cream. Drowsiness resulted in the premature discontinuation of the drug in approximately 5% of patients treated with Zonalon Cream in controlled clinical trials. Local Site Adverse Effects: In controlled clinical trials of patients treated with Zonalon Cream, the most common local site adverse event reported was burning and/or stinging at the site of application. These occurred in 76 of 330 (23%) of patients treated with Zonalon Cream compared to 54 of 334 (16%) of patients treated with vehicle cream. Most of these reactions were categorized as "mild"; however, approximately 25% of patients who reported burning and/or stinging reported the reaction as "severe". Four patients treated with Zonalon Cream withdrew from the study because of the burning and/or stinging. The table below presents the adverse events reported at an incidence of ≥ 1 % in either Zonalon or vehicle cream treatment groups during the trials: Adverse Event Zonalon N=330 Vehicle N=334 Burning /Stinging 76 (23.0%) 54 (16.2%) Drowsiness 71 (21.5%) 7 (2.1%) Dry Mouth1 32 (9.7%) 4 (1.2%) Pruritus2 13 (3.9%) 20 (6.0%) Fatigue/Tiredness 10 (3.0%) 5 (1.5%) Exacerbated Eczema 10 (3.0%) 8 (2.4%) Other Application Site Reaction3 10 (3.0%) 16 (4.8%) Dizziness4 7 (2.1%) 3 (0.9%) Mental Emotional Changes 6 (1.8%) 1 (0.3%) Taste Perversion5 5 (1.5%) 1 (0.3%) Edema 4 (1.2%) 1 (0.3%) Headache 3 (0.9%) 14 (4.2%) 1 Includes reports of “dry lips”, “dry throat”, and “thirst” 2Includes reports of “Pruritus Exacerbated” 3 Includes report of “increased irritation at application site” 4 Includes reports of “lightheadedness” and “dizziness/vertigo” 5 Includes reports of “bitter taste” and “metallic taste in mouth” Adverse events occurring in 0.5% to < 1.0% of Zonalon Cream treated patients in the controlled clinical trials included: nervousness/anxiety, tongue numbness, fever, and nausea. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Post Marketing Experience Twenty-six cases of allergic contact dermatitis have been reported in patients using Zonalon Cream, twenty of which were documented by positive patch test to doxepin 5% cream. OVERDOSAGE Deaths may occur from overdosage with this class of drugs. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations: Should overdosage with topical application of Zonalon Cream occur, the signs and symptoms may include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. General Recommendations: General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is strongly advised. If signs of toxicity occur at any time during this period, extended monitoring is recommended. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Cardiovascular: A maximal limb-lead QRS duration of >/=0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH>7.60 or a pCO 2 <20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION A thin film of Zonalon Cream should be applied four times each day with at least a 3 to 4 hour interval between applications. There are no data to establish the safety and effectiveness of Zonalon Cream when used for greater than 8 days. Chronic use beyond eight days may result in higher systemic levels and should be avoided. Use of Zonalon cream for longer than 8 days may result in an increased likelihood of contact sensitization. The risk for sedation may increase with greater body surface area application of Zonalon cream (See WARNINGS section). Clinical experience has shown that drowsiness is significantly more common in patients applying Zonalon Cream to over 10% of body surface area; therefore, patients with greater than 10% of body surface area (see WARNINGS section) affected should be particularly cautioned concerning possible drowsiness and other systemic adverse effects of doxepin. If excessive drowsiness occurs, it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings should not be utilized with Zonalon Cream. HOW SUPPLIED Zonalon Cream is available in 30 g (NDC 62436-523-30) and 45 g (NDC 62436-523-45) tubes. Store at or below 27° C (80° F). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Manufactured for: Bioglan Pharma, Inc. Malvern, PA 19355 by: DPT Laboratories, Inc. San Antonio, Texas 78215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 62436-523-30 Rx Only 111006 1102 UPC CODE Net Wt. 30g NDC 62436-523-30 Rx Only Net Wt. 30g Net Wt. 30g Net Wt. 30g Contains: Doxepin hydrochloride, USP, 5%, (equivalent to 4.4% doxepin) in a vehicle of sorbitol, cetyl alcohol, isopropyl myristate, glyceryl stearate, PEG-100 stearate, petrolatum, benzyl alcohol, titanium dioxide and purified water. Warnings: For External Use Only. Not For Ophthalmic Use. Keep away from eyes. Keep this and all drugs out of the reach of children. Directions: Apply a thin film of Zonalon Cream four times each day with at least a 3 to 4 hour interval between applications. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Manufactured for: Bioglan Pharmaceuticals Company, Malvern, PA 19355 by: DPT Laboratories, Ltd., San Antonio, Texas 78215 Warnings: For External Use Only. Not For Ophthalmic Use. Keep away from eyes. Keep this and all drugs out of the reach of children. Directions: Apply a thin film of Zonalon Cream four times each day with at least a 3 to 4 hour interval between applications. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Refer to product insert for prescribing information and inactive ingredient listing. Store Below 27°C (80°F) PHARMACEUTICALS PHARMACEUTICALS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 62436-523-30 Rx Only Manufactured for: Bioglan Pharmaceuticals Company, Malvern, PA 19355 by: DPT Laboratories, Ltd., San Antonio, Texas 78215 102359 1102 Warnings: For External Use Only. Not For Ophthalmic Use. Keep away from eyes. Keep this and all drugs out of the reach of children. Directions: Apply a thin film of Zonalon Cream four times each day with at least a 3 to 4 hour interval between applications. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Refer to product insert for prescribing information and inactive ingredient listing. Store Below 27°C (80°F) Net Wt. 30g PHARMACEUTICALS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PROFESSIONAL SAMPLE - NOT FOR RESALE Printed in U.S.A. NDC 62436-523-98 Rx Only NDC 62436-523-98 Rx Only Rx Only Rx Only WARNINGS: FOR EXTERNAL USE ONLY. NOT FOR OPHTHALMIC USE. KEEP AWAY FROM EYES. KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN. DIRECTIONS: Apply a thin film of Zonalon Cream four times each day with at least a 3 to 4 hour interval between applications. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Refer to product insert for prescribing information and inactive ingredient listing. STORE BELOW 27°C (80°F) CONTENTS: ACTIVE INGREDIENT: Doxepin Hydrochloride, 5% OTHER INGREDIENTS: Sorbitol, Cetyl Alcohol, Isopropyl Myristate, Glyceryl Stearate, PEG-100 Stearate, Petrolatum, Benzyl Alcohol, Titanium Dioxide, Purified Water. Manufactured for: Bioglan Pharmaceuticals Company Malvern, PA 19355 by: DPT Laboratories, Ltd. San Antonio, Texas 78215 133367 1202 30 & 45 gram tubes available 30 & 45 gram tubes available 30 & 45 gram tubes available 10 x 3g Tubes 10 x 3g Tubes 10 x 3g Tubes 10 x 3g Tubes 10 x 3g Tubes PHARMACEUTICALS PHARMACEUTICALS PHARMACEUTICALS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 62436-523-98 Professional Sample Rx ONLY Net Wt. 3g Warnings: For External Use Only. Not For Ophthalmic Use. Keep away from eyes. Keep this and all drugs out of the reach of children. Directions: Apply a thin film of Zonalon Cream four times each day with at least a 3 to 4 hour interval between applications. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Refer to product insert for prescribing information and inactive ingredient listing. Store Below 27°C (80°F) 102358 1102 Manufactured for: Bioglan Pharmaceuticals Company Malvern, PA 19355 by: DPT Laboratories, Ltd. San Antonio, Texas 78215 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 62436-523-45 Rx Only Net Wt. 45g Net Wt. 45g Net Wt. 45g Net Wt. 45g NDC 62436-523-45 Rx Only 111007 1102 UPC CODE Contains: Doxepin hydrochloride, USP, 5%, (equivalent to 4.4% doxepin) in a vehicle of sorbitol, cetyl alcohol, isopropyl myristate, glyceryl stearate, PEG-100 stearate, petrolatum, benzyl alcohol, titanium dioxide and purified water. Warnings: For External Use Only. Not For Ophthalmic Use. Keep away from eyes. Keep this and all drugs out of the reach of children. Directions: Apply a thin film of Zonalon Cream four times each day with at least a 3 to 4 hour interval between applications. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Manufactured for: Bioglan Pharmaceuticals Company, Malvern, PA 19355 by: DPT Laboratories, Ltd., San Antonio, Texas 78215 Warnings: For External Use Only. Not For Ophthalmic Use. Keep away from eyes. Keep this and all drugs out of the reach of children. Directions: Apply a thin film of Zonalon Cream four times each day with at least a 3 to 4 hour interval between applications. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Refer to product insert for prescribing information and inactive ingredient listing. Store Below 27°C (80°F) PHARMACEUTICALS PHARMACEUTICALS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 62436-523-45 Rx Only Warnings: For External Use Only. Not For Ophthalmic Use. Keep away from eyes. Keep this and all drugs out of the reach of children. Directions: Apply a thin film of Zonalon Cream four times each day with at least a 3 to 4 hour interval between applications. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Refer to product insert for prescribing information and inactive ingredient listing. Store Below 27°C (80°F) Manufactured for: Bioglan Pharmaceuticals Company, Malvern, PA 19355 by: DPT Laboratories, Ltd., San Antonio, Texas 78215 Net Wt. 45g 102360 1102 PHARMACEUTICALS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.209490	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20126slr006_Zonalon_lbl.pdf', 'application_number': 20126, 'submission_type': 'SUPPL ', 'submission_number': 6}
12,241	ProHance® (Gadoteridol) Injection, 279.3 mg/mL WARNING: NEPHROGENIC SYSTEMIC FIBROSIS Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs.  The risk for NSF appears highest among patients with:  chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or  acute kidney injury.  Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.  For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration (see WARNINGS). DESCRIPTION ProHance (Gadoteridol) Injection is a nonionic contrast medium for magnetic resonance imaging (MRI), available as a 0.5M sterile clear colorless to slightly yellow aqueous solution in vials and syringes for intravenous injection. Gadoteridol is the gadolinium complex of 10-(2-hydroxy-propyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid with a molecular weight of 558.7, an empirical formula of C17H29N4O7Gd and has the following structural formula: Each mL of ProHance contains 279.3 mg gadoteridol, 0.23 mg calteridol calcium, 1.21 mg tromethamine and water for injection. ProHance contains no antimicrobial preservative. ProHance has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below: PARAMETER Osmolality (mOsmol/kg water) @ 37° C 630 Viscosity (cP) @ 20° C 2.0 @ 37° C 1.3 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Specific Gravity @ 25° C 1.140 Density (g/mL) @ 25° C 1.137 Octanol: H2O coefficient -3.68 ± 0.02 ProHance has an osmolality 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use. CLINICAL PHARMACOLOGY Pharmacokinetics The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two- compartment open model with mean distribution and elimination half-lives (reported as mean ± SD) of about 0.20 ± 0.04 hours and 1.57 ± 0.08 hours, respectively. Gadoteridol is eliminated in the urine with 94.4 ± 4.8% (mean ± SD) of the dose excreted within 24 hours post-injection. It is unknown if biotransformation or decomposition of gadoteridol occur in vivo. The renal and plasma clearance rates (1.41 ± 0.33 mL/ min/kg and 1.50 ± 0.35 mL/ min/kg, respectively) of gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204 ± 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular filtration. It is unknown if protein binding of ProHance occurs in vivo. Pharmacodynamics Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent. In magnetic resonance imaging (MRI), visualization of normal and pathologic brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences. Gadoteridol does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of ProHance in various lesions is not known. CLINICAL TRIALS ProHance was evaluated in two blinded read trials in a total of 133 adults who had an indication for head and neck extracranial or extraspinal magnetic resonance imaging. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and < 1% other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% of the scans were enhanced. 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated. ProHance was evaluated in a multicenter clinical trial of 103 children who had an indication for a brain or spine MRI. These 103 children, (54 boys and 49 girls) had a mean age of 8.7 years with an age range of 2 to Page 2 of 8 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 years. Of these 103 children, 54 were between 2 and 12 years of age. Also, of these 103 children, 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. ProHance was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans. INDICATIONS AND USAGE Central Nervous System ProHance (Gadoteridol) Injection is indicated for use in MRI in adults and children over 2 years of age to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. Extracranial/Extraspinal Tissues ProHance is indicated for use in MRI in adults to visualize lesions in the head and neck. CONTRAINDICATIONS ProHance is contraindicated in patients with known allergic or hypersensitivity reactions to ProHance (see WARNINGS). WARNINGS Nephrogenic Systemic Fibrosis (NSF) Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ProHance administration to Bracco Diagnostics (1-800-257-5181) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Acute Kidney Injury (AKI) In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. Page 3 of 8 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypersensitivity Reactions Severe and fatal hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products, including ProHance. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely observed during the procedure and for several hours after drug administration. If a reaction occurs, stop ProHance and immediately begin appropriate therapy including resuscitation. (See PRECAUTIONS – General) Deoxygenated sickle erythrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by ProHance may possibly potentiate sickle erythrocyte alignment. ProHance in patients with sickle cell anemia and other hemoglobinopathies has not been studied. Patients with other hemolytic anemias have not been adequately evaluated following administration of ProHance to exclude the possibility of increased hemolysis. PRECAUTIONS General Diagnostic procedures that involve the use of contrast agents should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. Personnel trained in resuscitation techniques and resuscitation equipment should be available. The possibility of a reaction, including serious, life threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions (see ADVERSE REACTIONS), should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders. Gadoteridol is cleared from the body by glomerular filtration. The hepato-biliary enteric pathway of excretion has not been demonstrated with ProHance. Dose adjustments in renal or hepatic impairment have not been studied. Therefore, caution should be exercised in patients with either renal or hepatic impairment. In a patient with a history of grand mal seizure, the possibility to induce such a seizure by ProHance is unknown. When ProHance (Gadoteridol) Injection is to be injected using nondisposable equipment, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. After ProHance is drawn into a syringe, the solution should be used immediately. Repeat Procedures: Repeated procedures have not been studied. Sequential use during the same diagnostic session has only been studied in central nervous system use. (See Pharmacokinetics under CLINICAL PHARMACOLOGY and Central Nervous System under DOSAGE AND ADMINISTRATION). Information for patients: Patients scheduled to receive ProHance should be instructed to inform their physician if the patient; 1. is pregnant or breast feeding 2. has anemia or diseases that affect the red blood cells 3. has a history of renal or hepatic disease, seizure, hemoglobinopathies, asthma or allergic respiratory diseases 4. has recently received a GBCA. Page 4 of 8 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF: • Describe the clinical manifestations of NSF • Describe procedures to screen for the detection of renal impairment Instruct the patients to contact their physician if they develop signs or symptoms of NSF following ProHance administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY No animal studies have been performed to evaluate the carcinogenic potential of gadoteridol or potential effects on fertility. ProHance did not demonstrate genotoxic activity in bacterial reverse mutation assays using Salmonella typhimurium and Escherichia coli, in a mouse lymphoma forward mutation assay, in an in vitro cytogenetic assay measuring chromosomal aberration frequencies in Chinese hamster ovary cells, nor in an in vivo mouse micronucleus assay at intravenous doses up to 5.0 mmol/kg. Pregnancy Category C ProHance administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/m2 comparison) for 12 days during gestation doubled the incidence of postimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. ProHance increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/ kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2 comparison) for 13 days during gestation. There are no adequate and well-controlled studies in pregnant women. ProHance (Gadoteridol) Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ProHance is administered to a nursing woman. Pediatric Use Safety and efficacy in children under the age of 2 years have not been established. The safety and efficacy of doses > 0.1 mmol/kg; and sequential and/or repeat procedures has not been studied in children. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections) ADVERSE REACTIONS The adverse events described in this section were observed in clinical trials involving 1251 patients (670 males and 581 females). Adult patients ranged in age from 18-91 yrs. Pediatric patients ranged from 2-17 years. The racial breakdown was 83% Caucasian, 8% Black, 3% Hispanic, 2% Asian, and 1% other. In 2% of the patients, race was not reported. The most commonly noted adverse experiences were nausea and taste perversion with an incidence of 1.4%. These events were mild to moderate in severity. The following additional adverse events occurred in fewer than 1% of the patients: Body as a Whole: Facial Edema; Neck Rigidity; Pain; Pain at Injection Site; Injection Site Reaction; Chest Pain; Headache; Fever; Itching; Watery Eyes; Abdominal Cramps; Tingling Sensation in Throat; Laryngismus; Flushed Feeling; Vasovagal Reaction; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms) Cardiovascular: Prolonged P-R Interval; Hypotension; Elevated Heart Rate; A-V Nodal Rhythm Digestive: Edematous and/or itching tongue; Gingivitis; Dry Mouth; Loose Bowel; Vomiting Page 5 of 8 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervous System: Anxiety; Dizziness; Paresthesia; Mental Status Decline; Loss of Coordination in Arm; Staring Episode; Seizure; Syncope Respiratory System: Dyspnea; Rhinitis; Cough. Skin and Appendages: Pruritus; Rash; Rash Macular Papular; Urticaria; Hives; Tingling Sensation of Extremity and Digits Special Senses: Tinnitus The following adverse drug reactions have also been reported: Body as a Whole: Generalized Edema; Laryngeal Edema; Malaise; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms, and rarely resulting in Death). Cardiovascular: Cardiac Arrest; Bradycardia; Hypertension; and Death in association with pre-existing cardiovascular disorders. Digestive: Increased Salivation; Dysphagia Nervous System: Stupor; Tremor; Loss of Consciousness Respiratory: Apnea; Wheezing Skin and Appendages: Sweating; and Cyanosis Special Senses: Voice Alteration; Transitory Deafness Urogenital: Urinary Incontinence OVERDOSAGE Clinical consequences of overdose with ProHance have not been reported. DOSAGE AND ADMINISTRATION Central Nervous System ADULTS: The recommended dose of ProHance (Gadoteridol) Injection is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). In patients with normal renal function suspected of having poorly enhancing lesions, in the presence of negative or equivocal scans, a supplementary dose of 0.2 mmol/kg (0.4 mL/kg) may be given up to 30 minutes after the first dose. CHILDREN (2-18 years): The recommended dose of ProHance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). The safety and efficacy of doses > 0.1 mmol/kg, and sequential and/or repeat procedures has not been studied. Extracranial/Extraspinal Tissues ADULTS: The recommended dose of ProHance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). CHILDREN: Safety and efficacy for extracranial/extra-spinal tissues has not been established. Dose adjustments in renal and liver impairment have not been studied. To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour of the first injection of ProHance (Gadoteridol) Injection. Page 6 of 8 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials. HOW SUPPLIED ProHance (Gadoteridol) Injection is a clear, colorless to slightly yellow solution containing 279.3 mg/mL of gadoteridol in rubber stoppered vials. ProHance is available in boxes of: Five 5 mL fills in single dose 15 mL vials (NDC 0270-1111-04) Five 10 mL fills in single dose 30 mL vials (NDC 0270-1111-01) Five 15 mL fills in single dose 30 mL vials (NDC 0270-1111-02) Five 20 mL fills in single dose 30 mL vials (NDC 0270-1111-03) Five 10 mL fills in single dose 20 mL prefilled syringes (NDC 0270-1111-16) Five 17 mL fills in single dose 20 mL prefilled syringes (NDC 0270-1111-45) STORAGE ProHance (Gadoteridol) Injection should be stored at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Protect from light. DO NOT FREEZE. Should freezing occur in the vial, ProHance should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 60 minutes, ProHance (Gadoteridol) Injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard vial. Frozen syringes should be discarded. Directions for Use of the ProHance® (Gadoteridol) Injection single dose syringe* 1) Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few millimeters to break any friction between the cartridge plunger and syringe barrel. 2) Holding syringe erect, unscrew the plastic tip cap from the tip of the syringe and attach either a sterile, disposable needle or tubing with a compatible luer lock using a push-twist action. 3) Hold the syringe erect and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual aspiration procedure, complete the injection. To ensure complete delivery of the contrast medium, the injection should be followed by a normal saline flush. 4) Properly dispose of the syringe and any other materials used. *The syringe assembly is a HYPAK SCF® single dose syringe supplied by Becton Dickinson. Page 7 of 8 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 of 8 This product is covered by one or more of: U.S. Patent No. 5,474,756; U.S. Patent No. 5,846,519; and U.S. Patent No. 6,143,274. Manufactured for Bracco Diagnostics Inc. Monroe Twp., NJ 08831 by BIPSO GmbH 78224 Singen (Germany) F.1/XXXXXXX Revised August 2013 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance® Multipack™ (Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package - Not for Direct Infusion WARNING: NEPHROGENIC SYSTEMIC FIBROSIS Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs.  The risk for NSF appears highest among patients with:  chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or  acute kidney injury.  Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.  For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re- administration (see WARNINGS). DESCRIPTION ProHance (Gadoteridol) Injection is a nonionic contrast medium for magnetic resonance imaging (MRI), available as a 0.5M sterile clear colorless to slightly yellow aqueous solution for intravenous injection. Each vial is to be used as a Pharmacy Bulk Package for dispensing multiple single dose preparations utilizing a suitable transfer device. Gadoteridol is the gadolinium complex of 10-(2-hydroxy-propyl)-1,4,7,10- tetraazacyclododecane- 1,4,7-triacetic acid with a molecular weight of 558.7, an empirical formula of C17H29N4O7Gd and has the following structural formula: Each mL of ProHance contains 279.3 mg gadoteridol, 0.23 mg calteridol calcium, 1.21 mg tromethamine and water for injection. ProHance contains no antimicrobial preservative. ProHance has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below: PARAMETER Osmolality (mOsmol/kg water) @ 37° C 630 Viscosity (cP) @ 20° C 2.0 @ 37° C 1.3 Specific Gravity @ 25° C 1.140 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Density (g/mL) @ 25° C 1.137 Octanol: H2O coefficient -3.68 ± 0.02 ProHance has an osmolality 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use. CLINICAL PHARMACOLOGY Pharmacokinetics The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two- compartment open model with mean distribution and elimination half-lives (reported as mean ± SD) of about 0.20 ± 0.04 hours and 1.57 ± 0.08 hours, respectively. Gadoteridol is eliminated in the urine with 94.4 ± 4.8% (mean ± SD) of the dose excreted within 24 hours post-injection. It is unknown if biotransformation or decomposition of gadoteridol occur in vivo. The renal and plasma clearance rates (1.41 ± 0.33 mL/ min/kg and 1.50 ± 0.35 mL/ min/kg, respectively) of gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204 ± 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular filtration. It is unknown if protein binding of ProHance occurs in vivo. Pharmacodynamics Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent. In magnetic resonance imaging (MRI), visualization of normal and pathologic brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1- weighted sequences. Gadoteridol does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of ProHance in various lesions is not known. CLINICAL TRIALS ProHance was evaluated in two blinded read trials in a total of 133 adults who had an indication for head and neck extracranial or extraspinal magnetic resonance imaging. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and < 1% other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% of the scans were enhanced, 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated. ProHance was evaluated in a multicenter clinical trial of 103 children who had an indication for a brain or spine MRI. These 103 children, (54 boys and 49 girls) had a mean age of 8.7 years with an age range of 2 to 20 years. Of these 103 children, 54 were between 2 and 12 years of age. Also, of these 103 children, 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. ProHance was given in one single 0.1 mmol/kg Page 2 of 7 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans. In early studies, ProHance (Gadoteridol) Injection was evaluated in two multicenter trials of 310 evaluable patients suspected of having neurological pathology. After ProHance 0.1 mmol/kg IV, the results were similar to those described above. In another multicenter study of 49 evaluable adult patients with known intracranial tumor with high suspicion of having cerebral metastases, two doses of ProHance were administered. First ProHance 0.1 mmol/kg was injected followed 30 minutes later with 0.2 mmol/kg. In comparison to the 0.1 mmol/kg dose alone, the addition of the 0.2 mmol/kg dose improved visualization in 67% and improved border definition in 56% of patients. In comparison to non-contrast MRI, the number of lesions after 0.1 mmol/kg increased in 34% of patients. After ProHance 0.2 mmol/kg, this increased to 44%. INDICATIONS AND USAGE Central Nervous System ProHance (Gadoteridol) Injection is indicated for use in MRI in adults and children over 2 years of age to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. Extracranial/Extraspinal Tissues ProHance is indicated for use in MRI in adults to visualize lesions in the head and neck. CONTRAINDICATIONS ProHance is contraindicated in patients with known allergic or hypersensitivity reactions to ProHance (see WARNINGS). WARNINGS Nephrogenic Systemic Fibrosis (NSF) Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ProHance administration to Bracco Diagnostics (1-800-257-5181) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of Page 3 of 7 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hemodialysis in the prevention of NSF is unknown (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Acute Kidney Injury (AKI) In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. Hypersensitivity Reactions Severe and fatal hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products, including ProHance. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely observed during the procedure and for several hours after drug administration. If a reaction occurs, stop ProHance and immediately begin appropriate therapy including resuscitation. (See PRECAUTIONS – General) Deoxygenated sickle erythrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by ProHance may possibly potentiate sickle erythrocyte alignment. ProHance in patients with sickle cell anemia and other hemoglobinopathies has not been studied. Patients with other hemolytic anemias have not been adequately evaluated following administration of ProHance to exclude the possibility of increased hemolysis. PRECAUTIONS General Diagnostic procedures that involve the use of contrast agents should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. Personnel trained in resuscitation techniques and resuscitation equipment should be available. The possibility of a reaction, including serious, life threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions (see ADVERSE REACTIONS), should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders. Gadoteridol is cleared from the body by glomerular filtration. The hepato-biliary enteric pathway of excretion has not been demonstrated with ProHance. Dose adjustments in renal or hepatic impairment have not been studied. Therefore, caution should be exercised in patients with either renal or hepatic impairment. In a patient with a history of grand mal seizure, the possibility to induce such a seizure by ProHance is unknown. When ProHance (Gadoteridol) Injection is to be injected using nondisposable equipment, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. After ProHance is drawn into a syringe, the solution should be used immediately. Repeat Procedures: Repeated procedures have not been studied. Sequential use during the same diagnostic session has only been studied in central nervous system use. (See Pharmacokinetics under CLINICAL PHARMACOLOGY and Central Nervous System under DOSAGE AND ADMINISTRATION). Information for patients: Patients scheduled to receive ProHance should be instructed to inform their physician if the patient; Page 4 of 7 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1. is pregnant or breast feeding 2. has anemia or diseases that affect the red blood cells 3. has a history of renal or hepatic disease, seizure, hemoglobinopathies, asthma or allergic respiratory diseases 4. has recently received a GBCA. GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:  Describe the clinical manifestations of NSF  Describe procedures to screen for the detection of renal impairment Instruct the patients to contact their physician if they develop signs or symptoms of NSF following ProHance administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY No animal studies have been performed to evaluate the carcinogenic potential of gadoteridol or potential effects on fertility. ProHance did not demonstrate genotoxic activity in bacterial reverse mutation assays using Salmonella typhimurium and Escherichia coli, in a mouse lymphoma forward mutation assay, in an in vitro cytogenetic assay measuring chromosomal aberration frequencies in Chinese hamster ovary cells, nor in an in vivo mouse micronucleus assay at intravenous doses up to 5.0 mmol/kg. Pregnancy Category C ProHance administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/ m2 comparison) for 12 days during gestation doubled the incidence of postimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. ProHance increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/ kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2comparison) for 13 days during gestation. There are no adequate and well-controlled studies in pregnant women. ProHance (Gadoteridol) Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ProHance is administered to a nursing woman. Pediatric Use Safety and efficacy in children under the age of 2 years have not been established. The safety and efficacy of doses > 0.1 mmol/kg; and sequential and/or repeat procedures has not been studied in children. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections) ADVERSE REACTIONS The adverse events described in this section were observed in clinical trials involving 1251 patients (670 males and 581 females). Adult patients ranged in age from 18-91 yrs. Pediatric patients ranged from 2-17 years. The racial breakdown was 83% Caucasian, 8% Black, 3% Hispanic, 2% Asian, and 1% other. In 2% of the patients, race was not reported. The most commonly noted adverse experiences were nausea and taste perversion with an incidence of 1.4%. These events were mild to moderate in severity. Page 5 of 7 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The following additional adverse events occurred in fewer than 1% of the patients: Body as a Whole: Facial Edema; Neck Rigidity; Pain; Pain at Injection Site; Injection Site Reaction; Chest Pain; Headache; Fever; Itching; Watery Eyes; Abdominal Cramps; Tingling Sensation in Throat; Laryngismus; Flushed Feeling; Vasovagal Reaction; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms) Cardiovascular: Prolonged P-R Interval; Hypotension; Elevated Heart Rate; A-V Nodal Rhythm Digestive: Edematous and/or itching tongue; Gingivitis; Dry Mouth; Loose Bowel; Vomiting Nervous System: Anxiety; Dizziness; Paresthesia; Mental Status Decline; Loss of Coordination in Arm; Staring Episode; Seizure; Syncope Respiratory System: Dyspnea; Rhinitis; Cough Skin and Appendages: Pruritus; Rash; Rash Macular Papular; Urticaria; Hives; Tingling Sensation of Extremity and Digits Special Senses: Tinnitus The following adverse drug reactions have also been reported: Body as a Whole: Generalized Edema; Laryngeal Edema; Malaise; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms, and rarely resulting in Death) Cardiovascular: Cardiac Arrest; Bradycardia; Hypertension; and Death in association with pre-existing cardiovascular disorders Digestive: Increased Salivation; Dysphagia Nervous System: Stupor; Tremor; Loss of Consciousness Respiratory: Apnea; Wheezing Skin and Appendages: Sweating; and Cyanosis Special Senses: Voice Alteration; Transitory Deafness Urogenital: Urinary Incontinence OVERDOSAGE Clinical consequences of overdose with ProHance have not been reported. DOSAGE AND ADMINISTRATION Central Nervous System ADULTS: The recommended dose of ProHance (Gadoteridol) Injection is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). In patients with normal renal function suspected of having poorly enhancing lesions, in the presence of negative or equivocal scans, a supplementary dose of 0.2 mmol/kg (0.4 mL/kg) may be given up to 30 minutes after the first dose. CHILDREN (2-18 years): The recommended dose of ProHance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). The safety and efficacy of doses > 0.1 mmol/kg, and sequential and/or repeat procedures has not been studied. Extracranial/Extraspinal Tissues ADULTS: The recommended dose of ProHance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). CHILDREN: Safety and efficacy for extracranial/extra-spinal tissues has not been established. Dose adjustments in renal and liver impairment have not been studied. To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour of the first injection of ProHance (Gadoteridol) Injection. Page 6 of 7 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 of 7 DRUG HANDLING Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials. Concurrent medications or parenteral nutrition should not be physically mixed with contrast agents and should not be administered in the same intravenous line because of the potential for chemical incompatibility. Directions for Proper Use of ProHance (Gadoteridol) Injection Pharmacy Bulk Package The pharmacy bulk package is used as a multiple dose container with an appropriate transfer device to fill empty sterile syringes. ProHance Multipack Injection should be drawn into the syringe and administered using sterile technique. If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. Unused portions of the drug must be discarded. When ProHance Multipack Injection is to be injected using plastic disposable syringes, the agent should be drawn into the syringe and used immediately. 1. The transferring of ProHance (Gadoteridol) Injection from the Pharmacy Bulk Package should be performed in a suitable work area, such as a laminar flow hood, utilizing aseptic technique. 2. The container closure may be penetrated only one time, utilizing a suitable transfer device. Once the pharmacy bulk package is punctured, it should not be removed from the aseptic work area during the entire period of use. 3. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 8 hours from initial closure entry is permitted to complete fluid transfer operation. Any unused ProHance Multipack Injection must be discarded 8 hours after initial puncture of the bulk package. 4. Storage temperature of container after the closure has been entered should not exceed 25°C (77°F). HOW SUPPLIED ProHance (Gadoteridol) Injection is a clear, colorless to slightly yellow solution containing 279.3 mg/mL of gadoteridol in rubber stoppered vials. ProHance is available in boxes of five 50mL Pharmacy Bulk Packages (NDC 0270-1111-70). STORAGE ProHance (Gadoteridol) Injection should be stored at 25°C (77° F) excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Protect from light. DO NOT FREEZE. Should freezing occur in the vial, ProHance should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 60 minutes, ProHance (Gadoteridol) Injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard vial. This product is covered by one or more of: U.S. Patent No. 5,474,756; U.S. Patent No. 5,846,519; and U.S. Patent No. 6,143,274. Manufactured for Bracco Diagnostics Inc. Monroe Twp., NJ 08831 by BIPSO GmbH 78224 Singen (Germany) F.1/XXXXXXX Revised August 2013 Reference ID: 3356931 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.233967	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020131s026,021489s003lbl.pdf', 'application_number': 20131, 'submission_type': 'SUPPL ', 'submission_number': 26}
12,240	ProHance(8 Multipack™ (Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package -...Page 1 of9 Prohance Multipack (gadoteridol) Injection, Solution (Bracco Diagnostics Inc. i Pharmacy Bulk Package - Not for Direct Infusion WARNING: NEPHROGENIC SYSTEMIC FIBROSIS Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with: . acute or chronic severe renal insuffciency (glomerular filtration rate -:30 mL/min/1.73m2), or . acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a suffcient period of time for elimination of the agent from the body prior to any readministration (See WARNINGS). DESCRIPTION ProHance (Gadoteridol) Injection is a nonionic contrast medium for magnetic resonance imaging (MRI), available as a 0.5M sterile clear colorless to slightly yellow aqueous solution for intravenous injection. Each vial is to be used as a Pharmacy Bulk Package for dispensing multiple single dose preparations utilizing a suitable transfer device. Gadoteridol is the gadolinium complex of 1 0-(2-hydroxy-propyl)-1,4, 7,1 0-tetraazacyclododecane-1,4, 7- triacetic acid with a molecular weight of 558.7, an empirical formula of Ci 7H29N407Gd and has the following structural formula: Each mL of Pro Hance contains 279.3 mg gadoteridol, 0.23 mg calteridol calcium, 1.21 mg fie:/ /\ \Cdsesub 1 \n21489\S _ 001 \2007 -06-21 \ProHance Multipack NSF\spl\prohance _multi... 7/2012007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8 Multipack™ (Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package -... Page 2 of9 tromethamine and water for injection. ProHance contains no antimicrobial preservative. ProHance has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below: PARAMETER Osmolality (mOsmol/kg water) (i 370 C 630 Viscosity (cP) (i 200 C (i 370 C 2.0 1. Specific Gravity (i 250 C 1.140 Density (g/mL) (i 250 C Octanol: H20 coeffcient 1.37 -3.68 :! 0.02 ProHance has an osmolality 2.2 times that of plasma (285 mOsmollkg water) and is hypertonic under conditions of use. CLINICAL PHARMACOLOGY Pharmacokinetics The pharacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two- compartment open model with mean distribution and elimination half-lives (reported as mean:: SD) of about 0.20:: 0.04 hours and 1.57 :: 0.08 hours, respectively. Gadoteridol is eliminated in the urine with 94.4:: 4.8% (mean:: SD) of the dose excreted within 24 hours post-injection. It is unkown if biotransformation or decomposition of gadoteridol occur in vivo. The renal and plasma clearance rates (1.41 :: 0.33 mL/ min/kg and 1.50:: 0.35 mL/ min/kg, respectively) of gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204:: 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular fitration. It is unkown if protein binding of Pro Hance occurs in vivo. Pharmacodynamics Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent. In magnetic resonance imaging (MRI), visualization of normal and pathologic brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences. Gadoteridol does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrer, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrer or abnormal vascularity allows accumulation of file:/ /\ \Cdsesub 1 \n21489\S 001\2007-06-21 \Pro Hance Multipack NSF\spl\prohance multi... 7/2012007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(ß Multipack™ (Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package -... Page 3 of9 gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of ProHance in various lesions is not known. CLINICAL TRIALS ProHance was evaluated in two blinded read trials in a total of 133 adults who had an indication for head and neck extracranial or extraspinal magnetic resonance imaging. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and -: 1 % other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% of the scans were enhanced, 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated. ProHance was evaluated in a multicenter clinical trial of 103 children who had an indication for a brain or spine MRI. These.1 03 children, (54 boys and 49 girls) had a mean age of 8.7 years with an age range of2 to 20 years. Of these 103 children, 54 were between 2 and 12 years of age. Also, of these 103 children, 74% were Caucasian, 11 % Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. ProHance was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans. In early studies, ProHance (Gadoteridol) Inj ection was evaluated in two multicenter trals of 310 evaluable patients suspected of having neurological pathology. After ProHance 0.1 mmol/kg IV, the results were similar to those described above. In another multicenter study of 49 evaluable adult patients with known intracranial tumor with high suspicion of having cerebral metastases, two doses of Pro Hance were administered. First ProHance 0.1 mmol/kg was injected followed 30 minutes later with 0.2 mmol/kg. In comparison to the 0.1 mmol/kg dose alone, the addition of the 0.2 mmol/kg dose improved visualization in 67% and improved border definition in 56% of patients. In comparison to non-contrast MRI, the number of lesions after 0.1 mmol/kg increased in 34% of patients. After ProHance 0.2 mmol/kg, this increased to 44%. INDICATIONS AND USAGE Central Nervous System ProHance (Gadoteridol) Injection is indicated for use in MRI in adults and children over 2 years of age to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. ExtracraniaVExtraspinal Tissues ProHance is indicated for use in MRI in adults to visualize lesions in the head and neck. CONTRAINDICATIONS None known. WARINGS Nephrogenic Systemic Fibrosis (NSF) Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency (glomerular filtration rate -:30 mLimin/1.73m2) and in fie:/ /\ \Cdsesub 1 \n21489\S_ 001 \2007 -06- 21 \ProHance Multipack NSF\spl\prohance _multi... 7/2012007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8 Multipack™ (Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package -... Page 4 of 9 patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention ofNSF is unkown. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure. Post-marketing reports have identified the development ofNSF following single and multiple administrations of gadolinium-based contrast agents. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was gadodiamide (Omniscan TM), followed by gadopentetate dimeglumine (MagnevistCI) and gadoversetamide (OptiMARCI). NSF has also developed following sequential administrations of gadodiamide with gadobenate dimeglumine (MultiHanceCI) or gadoteridol (ProHanceCI). The number of post-marketing reports is subject to change over time and may not reflect the true proportion of cases associated with any specific gadolinium-based contrast agent. The extent of risk for NSF following exposure to any specific gadolinium-based contrast agent is unkown and may vary among the agents. Published reports are limited and predominantly estimate NSrr risks with gadodiamide. In one retrospective study of 370 patients with severe renal insufficiency who received gadodiamide, the estimated risk for development ofNSF was 4% (J Am Soc Nephrol 2006;17:2359). Tne risk, if any, for the development ofNSF among patients with mild to moderate renal insuffciency or normal renal function is unkown. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a suffcient period of time for elimination of the agent prior to any readministration. (See CLINICAL PHARlIACOLOGY and DOSAGE AND ADMINISTRt\TION). Deoxygenated sickle eryhrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by ProHance may possibly potentiate sickle erythrocyte alignment. ProHance in patients with sickle cell anemia and other hemoglobinopathies has not been studied. Patients with other hemolytic anemias have not been adequately evaluated following administration of ProHance to exclude the possibility of increased hemolysis. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely observed during the procedure and for several hours after drug administration. (See PRECAUTIO NS-General). PRECAUTIONS General. Gadoteridol is cleared from the body by glomerular fitration. The hepato-biliary enteric pathway of excretion has not been demonstrated with ProHaiice. Dose adjustments in renal or hepatic impairment have not been studied. Therefore, caution should be exercised in patients with either renal or hepatic impairment. In a patient with a history of grand mal seizure, the possibility to induce such a seizure by ProHance is unkown. +;1",. f/\ \ r'r1",,,.mh 1\1'7 1 L1~Q\i; nn1 \7nn7 nh 71 \PmH~nr.p, Mii ltimiek NSF\snl\nrohance multi... 7/20/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8 Multipack™ (Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package -... Page 5 of9 The possibility of a reaction, including serious, life threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions (see ADVERSE REACTIONS), should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders. Diagnostic procedures that involve the use of contrast agents should be carred out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. When ProHance (Gadoteridol) Injection is to be injected using nondisposable equipment, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. After ProHance is drawn into a syrnge, the solution should be used immediately. Repeat Procedures: Repeated procedures have not been studied. Sequential use during the same diagnostic session has only been studied in central nervous system use. (See Pharmacokinetics under CLINICAL PHARMACOLOGY and Central Nervous System under DOSAGE AND ADMINISTRATION). Information for patients: Patients scheduled to receive ProHance should be instructed to inform their physician if the patient; 1. is pregnant or breast feeding 2. has anemia or diseases that affect the red blood cells 3. has a history of renal or hepatic disease, seizure, hemoglobinopathies, asthma or allergic respiratory diseases. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY No animal studies have been performed to evaluate the carcinogenic potential of gadoteridol or potential effects on fertility. ProHance did not demonstrate genotoxic activity in bacterial reverse mutation assays using Salmonella typhimurium and Escherichia coli, in a mouse lymphoma forward mutation assay, in an in vitro cytogenetic assay measuring chromosomal aberration frequencies in Chinese hamster ovary cells, nor in an in vivo mouse micronucleus assay at intravenous doses up to 5.0 mmol/kg. Pregnancy Category C ProHance administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/m2 comparison) for 12 days during gestation doubled the incidence of post implantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. ProHance increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2 comparison) for 13 days during gestation. There are no adequate and well-controlled studies in pregnant women. ProHance (Gadoteridol) Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ProHance is administered to a nursing woman. fie:/ /\ \Cdsesub 1 \n21489\S _ 001 \2007 -06- 21 \ProHance Multipack NSF\spl\prohance _multi... 7/20/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8 Multipack™(Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package -... Page 60f9 Pediatric Use Safety and effcacy in children under the age of 2 years have not been established. The safety and efficacy of doses :: 0.1 mmol/kg; and sequential and/or repeat procedures has not been studied in children. (See INDICATIONS AND USAGE and DOSAGE AND ADl\lINISTRATION sections) ADVERSE REACTIONS The adverse events described in this section were observed in clinical trials involving 1251 patients (670 males and 581 females). Adult patients ranged in age from 18-91 yr. Pediatric patients ranged from 2- 17 years. The racial breakdown was 83%Caucasian, 8% Black, 3% Hispanic, 2% Asian, and 1 % other. In 2% ofthe patients, race was not reported. The most commonly noted adverse experiences were nausea and taste perversion with an incidence of 1.4%. These events were mild to moderate in severity. The following additional adverse events occurred in fewer than 1 % of the patients: Special Senses: Facial Edema; Neck Rigidity; Pain; Pain at Injection Site; Injection Site Reaction; Chest Pain; Headache; Fever; Itching; Watery Eyes; Abdominal Cramps; Tingling Sensation in Throat; Larygismus; Flushed Feeling; Vasovagal Reaction; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms) . Prolonged P-R Interval; Hypotension; Elevated Heart Rate; A-V Nodal Rhythm Edematous and/or itching tongue; Gingivitis; Dry Mouth; Loose Bowel; Vomiting Anxiety; Dizziness; Paresthesia; Mental Status Decline; Loss of Coordination in Ann; Staring Episode; Seizure; Syncope Dyspnea; Rhinitis; Cough Pruritus; Rash; Rash Macular Papular; Urticaria; Hives; Tingling Sensation of Extremity and Digits; Sweating; and Cyanosis Tinnitus Body as a Whole: Cardiovascular: Digestive: Nervous System: Respiratory System: Skin and Appendages: The following adverse drug reactions have also been reported: Cardiovascular: Generalized Edema; Laryngeal Edema; Malaise; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms, and rarely resulting in Death) Cardiac Arrest; Bradycardia; Hypertension; and Death in association with pre-existing cardiovascular disorders Increased Salivation; Dysphagia Stupor; Tremor; Loss of Consciousness Apnea; Wheezing Sweating; and Cyanosis Voice Alteration; Transitory Deafness Urinary Incontinence Body as a Whole: Digestive: Nervous System: Respiratory: Skin and Appendages: Special Senses: Urogenital: OVERDOSAGE Clinical consequences of overdose with ProHance have not been reported. DOSAGE AND ADMINISTRATION Central Nervous System ADULTS: The recommended dose of Pro Hance (Gadoteridol) Injection is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (l0 mL/min-60 mL/min) or bolus (:: 60 mL/min). In me:/ /\ \~rlsesuh 1 \n21489\S 001\2007-06-21 \ProHance Multipack NSF\spl\prohance multi... 7120/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHaiice(8 Multipack™ (Gadoteridol)Injection, 279.3 mg/mL Pharmacy Bulk Package -... Page 7 of9 patients suspected of having poorly enhancing lesions, in the presence of negative or equivocal scans, a second dose of 0.2 mmollkg (0.4 mL/kg) may be given up to 30 minutes after the first dose. CHILDREN (2-18 years): The recommended dose of Pro Hance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (:: 60 mL/min). The safety and effcacy of doses :: 0.1 mmol/kg, and sequential and/or repeat procedures has not been studied. ExtracraniaUExtraspinal Tissues ADULTS: The recommended dose of Pro Hance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (:: 60 mL/min). CHILDREN: Safety and effcacy for extracranial/extra-spinal tissues has not been established. Dose adjustments in renal and liver impairment have not been studied. To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour ofthe first injection of ProHance (Gadoteridol) Injection. DRUG HANDLING Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials. Concurent medications or parenteral nutrition should not be physically mixed with contrast agents and should not be administered in the same intravenous line because of the potential for chemical incompatibility Directions for Proper Use of ProHaiice (Gadoteridol) Injection Pharmacy Bulk Package The pharmacy bulk package is used as a multiple dose container with an appropriate transfer device to fill empty sterile syringes. ProHance Multipack Injection should be drawn into the syringe and administered using sterile technique. If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. Unused portions of the drug must be discarded. When ProHance Multipack Injection is to be injected using plastic disposable syringes, the agent should be drawn into the syrnge and used immediately. a. The transferring of Pro Hance (Gadoteridol) Injection from the Pharmacy Bulk Package should be performed in a suitable work area, such as a laminar flow hood, utilizing aseptic technique. b. The container closure may be penetrated only one time, utilizing a suitable transfer device. Once the pharmacy bulk package is punctured, it should not be removed from the aseptic work area during the entire period of use. c. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 8 hours from initial closure entry is permitted to complete fluid transfer operation. Any unused ProHance Multipack Injection must be discarded 8 hours after initial puncture of the bulk package. d. Storage temperature of container after the closure has been entered should not exceed 25° C (77° F). HOW SUPPLIED fie:/ /\ \Còsesnh 1 \n21489\S 001\2007-06-21 \ProHance Multipack NSF\spl\prohance multi... 7/20/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8 Multipack™ (Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package -... Page 8 of 9 ProHance (Gadoteridol) Injection is a clear, colorless to slightly yellow solution containing 279.3 mg/mL of gadoteridol in rubber stoppered vials. ProHance is available in boxes of five 50mL Pharmacy Bulk Packages (NDC 0270-1111-70). STORAGE ProHance (Gadoteridol) Injection should be stored at 25°C (77°F) excursions permitted to 15-30°C (59- 86°F) (See USP Controlled Room Temperature). Protect from light. DO NOT FREEZE. Should freezing occur in the vial, ProHance should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 60 minutes, ProHance (Gadoteridol) Injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard viaL. This product is covered by one or more of: U.S. Patent No. 4,885,363; U.S. Patent No. 4,963,344; U.S. Patent No. 5,474,756; U.S. Patent No. 5,846,519; and U.S. Patent No. 6,143,274. Manufactured for Bracco Diagnostics Inc. Princeton, NJ 08543 by ALTANAPharmaAG 78224 Singen (Germany) Revised May 2007 Fl/3.5524.53 .......v....,""...w._......v".. "". ..m ... ......_.........~....u.. ..................................... ..............._......m...~.~. ................................. .". ......n..........~......w...... ProHance Multipack (gadoteridol) PRODUCT INFO Product Code 0270-1111 Dosage Form INJECTION, SOLUTION .,.."''''''''''~m'=''=='..,'.'=~,,.,''== Route Of Administration INTRAVENOUS DEA Schedule INGREDIENTS Name (Active Moiety) gadoteridol (gadoterido1) calteridol calcium tromethamine Type Strength 279.3 MILLIGRAM In 1 MILLILITER .23 MILLIGRA In 1 MILLILITER 1.21 MILLIGRAM In 1 MILLILITER Active Inactive Inactive IMPRINT INFORMATION Characteristic Appearance Color Characteristic Appearance Score Shape Imprint Code Size Symbol Coating fie:/ /\ \Cdsesub 1 \n21489\S _ 001 \2007 -06-2 i \ProHance Multipack NSF\spl\prohance _multi... 7/2012007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8 Multipack™ (Gadoteridol) Injection, 279.3 mg/mL Pharmacy Bulk Package -... Page 9 of 9 PACKAGING # NDC 1 1 Revised: 04/2006 Package Description 5 VIAL In 1 BOX 50 MILLILITER In 1 VIAL, PHARMACY BULK PACKAGE Multilevel Packaging contains a VIAL, PHARMACY BULK PACKAGE This package is contained within the BOX (0270-1111-70) Bracco Diagnostics Inc. fie://\ \Cdsesub 1 \n21489\S _ 001 \2007 -06-21 \ProHance Multipack NSF\spl\prohance _multi... 7/20/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8( Gadoterido 1 Inj ection) Page 1 of9 Prohance (gadoteridol) Injection, Solution (Bracco Diagnostics Inc. i WARNING: NEPHROGENIC SYSTEMIC FIBROSIS Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with: . acute or chronic severe renal insuffciency (glomerular filtration rate -: 30 mL/min/1.73m2), or . acute renal insuffciency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a suffcient period oftime for elimination of the agent from the body prior to any readministration (See WARINGS). DESCRIPTION ProHance (Gadoteridol) Injection is a nonionic contrast medium for magnetic resonance imaging (MRI), available as a 0.5M sterile clear colorless to slightly yellow aqueous solution in vials and syringes for intravenous injection. Gadoteridol is the gadolinium complex of 1 0-(2-hydroxy-propyl)-1,4, 7,10- tetraazacyclododecane-1,4, 7- triacetic acid with a molecular weight of 558.7, an empirical formula OfC17H29N407Gd and has the following structural formula: o Each mL of Pro Hance contains 279.3 mg gadoteridol, 0.23 mg calteridol calcium, 1.21 mg tromethamine and water for injection. ProHance contains no antimicrobial preservative. ProHance has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below: PARAMETER Osmolality (mOsmol/kg water) (i 370 C 630 Viscosity fie:/ /\ \Cdsesub 1 \n20131 \S _ 023\2007 -06-21\ProHance NSF\spl\prohance.xml 9/4/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8( Gadoteridol Inj ection) Page 2 of9 (cP) (i 200 C 2.0 (i 370 C 1. Specific Gravity (i 250 C 1.40 Density (g/mL) (i 250 C 1.37 Octanol: H20 coeffcient-3.68:! 0.02 ProHance has an osmolality 2.2 times that of plasma (285 mOsmollkg water) and is hypertonic under conditions of use. CLINICAL PHARACOLOGY Pharmacokinetics The pharacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two- compartment open model with mean distribution and elimination half-lives (reported as mean:: SD) of about 0.20:: 0.04 hours and 1.57:: 0.08 hours, respectively. Gadoteridol is eliminated in the urine with 94.4 :: 4.8% (mean:: SD) ofthe dose excreted within 24 hours post-injection. It is unkown if biotransformation or decomposition of gadoteridol occur in vivo. The renal and plasma clearance rates (1.41 :: 0.33 mL/ min/kg and 1.50:: 0.35 mL/ min/kg, respectively) of gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204:: 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular fitration. It is unkown if protein binding of Pro Hance occurs in vivo. Pharmacodynamics Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent. . In magnetic resonance imaging (MRI), visualization of normal and pathologic brain tissue depends in part on variations in the radio frequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences. Gadoteridol does not cross the intact blood-brain barrer and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrer or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of ProHance in various lesions is not known. CLINICAL TRIALS ProHance was evaluated in two blinded read trials in a total of 133 adults who had an indication for head fie:/ /\ \Cdsesub 1 \n20 13 i \S _ 023\2007 -06-21 \ProHance NSF\spl\prohance.xml 9/4/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8( Gadoteridol Inj ection) Page 3 of9 and neck extracranial or extraspinal magnetic resonance imaging. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and -: 1 % other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% ofthe scans were enhanced. 45-48% of the scans provided additional diagnostic information, and 8-25% ofthe diagnoses were changed. The relevance ofthe findings to disease sensitivity and specificity has not been fully evaluated. ProHance was evaluated in a multicenter clinical trial of 103 children who had an indication for a brain or spine MRI. These 103 children, (54 boys and 49 girls) had a mean age of8.7 years with an age range of 2 to 20 years. Ofthese 103 children, 54 were between 2 and 12 years of age. Also, ofthese 103 children, 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. ProHance was given in one single 0.1 mmol/g dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans. INDICATIONS AND USAGE Central Nervous System ProHance (Gadoteridol) Injection is indicated for use in MRI in adults and children over 2 years of age to visualize lesions with abnormal vascularity in the brain (intracranial lesions ), spine and associated tissues. ExtracraniallExtraspinal Tissues ProHance is indicated for use in MRI in adults to visualize lesions in the head and neck. CONTRAINDICATIONS None known. WARINGS Nephrogenic Systemic Fibrosis (NSF) Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insuffciency (glomerular filtration rate ~30 mL/min/1. 73m2) and in patients with acute renal insuffciency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention ofNSF is unkown. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure. Post-marketing reports have identified the development ofNSF following single and multiple administrations of gadolinium-based contrast agents. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was gadodiamide (Omniscan TM), followed by gadopentetate dimeglumine (MagnevistCI) and gadoversetamide (OptiMAR(ß). NSF has also developed following sequential administrations of gadodiamide with gadobenate dimeglumine (MultiHanceCI) or gadoteridol (ProHanceCI). The number of post-marketing file:/ /\ \Cdsesub 1 \n20131 \S _ 023\2007 -06-21 \ProHance NSF\spl\prohance.xml 9/4/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8( Gadoteridol Inj ection) Page 4 of9 reports is subject to change over time and may not reflect the true proportion of cases associated with any specific gadolinium-based contrast agent. The extent of risk for NSF following exposure to any specific gadolinium-based contrast agent is unkown and may vary among the agents. Published reports are limited and predominantly estimate NSF risks with gadodiamide. In one retrospective study of 370 patients with severe renal insuffciency who received gadodiamide, the estimated risk for development ofNSF was 4% (J Am Soc Nephrol 2006;17:2359). The risk, if any, for the development ofNSF among patients with mild to moderate renal insuffciency or normal renal function is unkown. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a suffcient period of time for elimination of the agent prior to any readministration. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Deoxygenated sickle eryhrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by ProHance may possibly potentiate sickle eryhrocyte alignment. ProHance in patients with sickle cell anemia and other hemoglobinopathies has not been studied. Patients with other hemolytic anemias have not been adequately evaluated following administration of ProHance to exclude the possibility of increased hemolysis. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely observed during tne procedure and for several hours after dmg administration. (See PRECAUTIONS-GeneraJ). PRECAUTIONS General Gadoteridol is cleared ftom the body by glomerular filtration. The hepato-biliary enteric pathway of excretion has not been demonstrated with ProHanceCI. Dose adjustments in renal or hepatic impairment have not been studied. Therefore, caution should be exercised in patients with either renal or hepatic impairment. In a patient with a history of grand mal seizure, the possibility to induce such a seizure by ProHanceCI is unkown. The possibility of a reaction, including serious, life threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions (see ADVERSE REACTIONS), should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders. Diagnostic procedures that involve the use of contrast agents should be carred out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. When ProHance (Gadoteridol) Injection is to be injected using nondisposable equipment, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. After ProHance is drawn into a syringe, the solution should be used immediately. Repeat Procedures: Repeated procedures have not been studied. Sequential use during the same diagnostic session has only been studied in central nervous system use. (See Pharmacokinetics under CLINICAL PHARMACOLOGY and Central Nervous System under DOSAGE AND ADMINISTRATION). file:/ /\ \Cdsesub 1 \n20 13 i \S _ 023\2007 -06-21 \ProHance NSF\spl\prohance.xml 9/412007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(8(Gadoteridol Injection) Page 5 of9 Information for patients: Patients scheduled to receive ProHance should be instructed to inform their physician if the patient; 1. is pregnant or breast feeding 2. has anemia or diseases that affect the red blood cells 3. has a history of renal or hepatic disease, seizure, hemoglobinopathies, asthma or allergic respiratory diseases. CARCINOGENESIS, MUTAGENESIS, ANn IMPAIRMENT OF FERTILITY No animal studies have been performed to evaluate the carcinogenic potential of gadoteridol or potential effects on fertility. ProHance did not demonstrate genotoxic activity in bacterial reverse mutation assays using Salmonella typhimurium and Escherichia coli, in a mouse lymphoma forward mutation assay, in an in vitro cytogenetic assay measuring chromosomal aberration frequencies in Chinese hamster ovary cells, nor in an in vivo mouse micronucleus assay at intravenous doses up to 5.0 mmol/kg. Pregnancy Category C ProHance administered to rats at 10 mmollkg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/ m2 comparison) for 12 days during gestation doubled the incidence ofpostimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. ProHance increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/ kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2 comparison) for 13 days during gestation. There are no adequate and well-controlled studies in pregnant women. ProHance (Gadoteridol) Injection should be used during pregnancy only ifthe potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ProHance is administered to a nursing woman. Pediatric Use Safety and effcacy in children under the age of 2 years have not been established. The safety and effcacy of doses? 0.1 mmol/kg; and sequential and/or repeat procedures has not been studied in children. (See INDICATIONS AND USAGE and DOSAGE AND AD1VUNISTRATION sections) ADVERSE REACTIONS The adverse events described in this section were observed in clinical trials involving 1251 patients (670 males and 581 females). Adult patients ranged in age from 18-91 yrs. Pediatric patients ranged from 2- 17 years. The racial breakdown was 83% Caucasian, 8% Black, 3% Hispanic, 2% Asian, and 1 % other. In 2% ofthe patients, race was not reported. The most commonly noted adverse experiences were nausea and taste perversion with an incidence of 1.4%. These events were mild to moderate in severity. fie:/ /\ \Cdsesub 1 \n20 13 1 \S _ 023 \2007 -06- 21 \ProHance NSF\spl\prohance.xml 9/4/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(I(Gadoteridol Injection) Page 6 of9 The following additional adverse events occurred in fewer than 1 % of the patients: Special Senses: Facial Edema; Neck Rigidity; Pain; Pain at Injection Site; Injection Site Reaction; Chest Pain; Headache; Fever; Itching; Watery Eyes; Abdominal Cramps; Tingling Sensation in Throat; Larygismus; Flushed Feeling; Vasovagal Reaction; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms) Prolonged P-R Interval; Hypotension; Elevated Heart Rate; A-V Nodal Rhythm Edematous and/or itching tongue; Gingivitis; Dry Mouth; Loose Bowel; Vomiting Anxiety; Dizziness; Paresthesia; Mental Status Decline; Loss of Coordination in Arm; Staring Episode; Seizure; Syncope Dyspnea; Rhinitis; Cough. Pruritus; Rash; Rash Macular Papular; Urticaria; Hives; Tingling Sensation of Extremity and Digits Tinnitus Body as a Whole: Cardiovascular: Digestive: Nervous System: Respiratory System: Skin and Appendages: The following adverse drug reactions have also been reported: Cardiovascular: Generalized Edema; Larygeal Edema; Malaise; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms, and rarely resulting in Death). Cardiac Arrest; Bradycardia; Hypertension; and Death in association with pre-existing cardiovascular disorders. Increased Salivation; Dysphagia Stupor; Tremor; Loss of Consciousness Apnea; Wheezing Sweating; and Cyanosis Voice Alteration; transitory deafness Urinary Incontinence Body as a Whole: Digestive: Nervous System: Respiratory: Skin and Appendages: Special Senses: Urogenital: OVERDOSAGE Clinical consequences of overdose with ProHance have not be~n reported. DOSAGE AND ADMINISTRATION Central Nervous System ADULTS: The recommended dose of Pro Hance (Gadoteridol) Injection is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (? 60 mL/min). In patients suspected of having poorly enhancing lesions, in the presence of negative or equivocal scans, a second dose of 0.2 mmol/g (0.4 mL/kg) may be given up to 30 minutes after the first dose. CHILDREN (2-18 years): The recommended dose ofProHanceCI is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (? 60 mL/min). The safety and effcacy of doses? 0.1 mmol/kg, and sequential and/or repeat procedures has not been studied. ExtracraniaVExtraspinal Tissues ADUL TS: The recommended dose of Pro Hance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus ( ? 60 mL/min). CHILDREN: Safety and efficacy for extracraniallextra-spinal tissues has not been established. Dose adjustments in renal and liver impairment have not been studied. fie:/ /\ \Cdsesub 1 \n20131 \S _ 023\2007 -06-21 \ProHance NSF\spl\prohance.xml 9/412007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(I(Gadoteridol Injection) Page 7 of9 To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour of the first injection of ProHance (Gadoteridol) Injection. Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matterIs present. Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials. HOW SUPPLIED ProHance (Gadoteridol) Injection is a clear, colorless to slightly yellow solution containing 279.3 mg/mL of gadoteridol in rubber stoppered vials. ProHance is available in boxes of: Five 5 mL fills in single dose 15 mL vials Five 10 mL fills in single dose 30 mL vials Five 15 mL fills in single dose 30 mL vials Five 20 mL fills in single dose 30 mL vials Five 10 mL fills in single dose 20 mL prefilled syrnges Five 17 mL fills in single dose 20 mL prefilled syrnges (NDc 0270-1111-04) (NDc 0270- 1 ILL -01) (Nc 0270- 1 11 1 -02) (NDc 0270- 1 1 1 1 -03) (Nc 0270- 1111-16) . (Nc 0270- 1 1 1 1 -45) STORAGE ProHance (Gadoteridol) Injection should be stored at 25° C (77° F) excursions permitted to 15-30° C (59-86° F) (See USP Controlled Room Temperature). Protect from light. DO NOT FREEZE. Should freezing occur in the vial, ProHance should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 60 minutes, ProHance (Gadoteridol) Injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard viaL. Frozen syringes should be discarded. . Directions for Use of the ProHanceCI (Gadoteridol) Injection single dose syringe* 1) Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few milimeters to break any friction between the cartridge plunger and syrnge barreL. Ru Carrri 2) Holding syrnge erect, aseptically remove the rubber cap from the tip of the syrnge and attach either a sterile, disposable needle or tubing with a compatible luer lock using a push-twist action. 3) Hold the syrnge erect and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual aspiration procedure, complete fie:/ /\ \Cdsesub 1 \n20 i 31 \S _ 023\2007 -06-21 \ProHance NSF\spl\prohance.xml 9/4/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(I(Gadoteridol Injection) Page 8 of9 the injection. To ensure complete delivery of the contrast medium, the injection should be followed by a normal saline flush. 4) Properly dispose ofthe syringe and any other materials used. This product is covered by one or more of: U.S. Patent No. 4,885,363; U.S. Patent No. 4,963,344; U.S. Patent No. 5,474,756; U.S. Patent No. 5,846,519; and U.S. Patent No. 6,143,274. *The syrnge assembly is a HYP AK SCFCI single dose syringe supplied by Becton Dickinson. Manufactured for Bracco Diagnostics Inc. Princeton, NJ 08543 by ALTANAPharmaAG 78224 Singen (Germany) Revised May 2007 F1I3.5524.44 ___~~.~_.m__..".. ._.............. ........-."..._......... ...~.._.._~..__.mnmnn.__...~.....g m.................nm......_.n...w_mvm..~v.....~ .w..nm...m..d.n.....n........"'''m.n....._.. ...............................__.m....................w.................................~..m......_..............m..m..m ................m........._........................ mm...._...mm..nm........................_.._......m.............._..............._.m.....__..............m......................................._m..........................__.......m..._.._..............................................w............................_...n.__............n.....__._....~.......................................m.........__~~~"m~.____...,...__._~.__..m.D Pro Hance (gadoteridol) PRODUCT INFO Product Code 0270-1111 Dosage Form INJECTION, SOLUTION Route Of Administration INTRAVENOUS DEA Schedule INGREDIENTS Name (Active Moiety) gadoteridol (gadoterido1) calteridol calcium Type Strength 279.3 MILLIGRAM In 1 MILLILITER 0.23 MILLIGRAM In 1 MILLILITER 1.21 MILLIGRAM In 1 MILLILITER tromethamine Active Inactive Inactive IMPRINT INFORMATION Characteristic Appearance Color Shape Imprint Code Size Characteristic Appearance Score Symbol Coating PACKAGING # NDC 1 0270-1111-04 1 2 0270-1111-01 2 Package Description 5 VIAL In 1 BOX 5 MILLILITER In 1 VIAL, SINGLE-DOSE 1 BOX Multilevel Packaging contains a VIAL, SINGLE-DOSE ackage is contained within the BOX (0270-1111-04) L, SINGLE-DOSE fie:/ /\ \Cdsesub 1 \n20 131 \S _ 023\2007 -06- 21 \ProHance NSF\spl\prohance.xml 9/4/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ProHance(I( Gadoteridol Inj ection) Page 9 of9 5 VIAL In 1 BOX contains a VIAL, SINGLE-DOSE 15 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the BOX (0270- 1111-02) In 1 BOX contains a VIAL, SINGLE-DOSE VIAL, SINGLE-DOSE package is contained within the BOX (0270-1111-03) 5 0270-1111-16 GEIn 1 BOX contains a SYRIGE, GLASS 5 10 MILLILITER In 1 SYRGE, GLASS This package is contained within the BOX (0270-1111-16) 6 0270-1111-45 5 SYRIGE In 1 BOX contains a SYRIGE, GLASS 6 17 MILLILITER In 1 SYRINGE, GLASS This package is contained within the BOX (0270-1111-45) -- Revised: 04/2006 Bracco Diagnostics Inc. fie:/ /\ \Cdsesub 1 \n0 131 \S _ 023 \2007 -06- 21 \ProHance NSF\spl\prohance.xml 9/4/2007 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.354969	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020131s023,021489s001lbl.pdf', 'application_number': 20131, 'submission_type': 'SUPPL ', 'submission_number': 23}
12,243	NDA 20136/S-023 Page 3 Demadex (torsemide) Tablets DESCRIPTION Demadex (torsemide) is a diuretic of the pyridine-sulfonylurea class. Its chemical name is 1 isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl] urea and its structural formula is: Structural Formula Its empirical formula is C16H20N4O3S, its pKa is 7.1, and its molecular weight is 348.43. Torsemide is a white to off-white crystalline powder. The tablets for oral administration also contain lactose NF, crospovidone NF, povidone USP, microcrystalline cellulose NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action Micropuncture studies in animals have shown that torsemide acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the Na+/K+/2CI--carrier system. Clinical pharmacology studies have confirmed this site of action in humans, and effects in other segments of the nephron have not been demonstrated. Diuretic activity thus correlates better with the rate of drug excretion in the urine than with the concentration in the blood. Torsemide increases the urinary excretion of sodium, chloride, and water, but it does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance. Pharmacokinetics and Metabolism The bioavailability of Demadex tablets is approximately 80%, with little intersubject variation; the 90% confidence interval is 75% to 89%. The drug is absorbed with little first-pass metabolism, and the serum concentration reaches its peak (Cmax) within 1 hour after oral administration. Cmax and area under the serum concentration-time curve (AUC) after oral administration are proportional to dose over the range of 2.5 mg to 200 mg. Simultaneous food intake delays the time to Cmax by about 30 minutes, but overall bioavailability (AUC) and diuretic activity are unchanged. Absorption is essentially unaffected by renal or hepatic dysfunction. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 4 The volume of distribution of torsemide is 12 liters to 15 liters in normal adults or in patients with mild to moderate renal failure or congestive heart failure. In patients with hepatic cirrhosis, the volume of distribution is approximately doubled. In normal subjects the elimination half-life of torsemide is approximately 3.5 hours. Torsemide is cleared from the circulation by both hepatic metabolism (approximately 80% of total clearance) and excretion into the urine (approximately 20% of total clearance in patients with normal renal function). The major metabolite in humans is the carboxylic acid derivative, which is biologically inactive. Two of the lesser metabolites possess some diuretic activity, but for practical purposes metabolism terminates the action of the drug. Because torsemide is extensively bound to plasma protein (>99%), very little enters tubular urine via glomerular filtration. Most renal clearance of torsemide occurs via active secretion of the drug by the proximal tubules into tubular urine. In patients with decompensated congestive heart failure, hepatic and renal clearance are both reduced, probably because of hepatic congestion and decreased renal plasma flow, respectively. The total clearance of torsemide is approximately 50% of that seen in healthy volunteers, and the plasma half-life and AUC are correspondingly increased. Because of reduced renal clearance, a smaller fraction of any given dose is delivered to the intraluminal site of action, so at any given dose there is less natriuresis in patients with congestive heart failure than in normal subjects. In patients with renal failure, renal clearance of torsemide is markedly decreased but total plasma clearance is not significantly altered. A smaller fraction of the administered dose is delivered to the intraluminal site of action, and the natriuretic action of any given dose of diuretic is reduced. A diuretic response in renal failure may still be achieved if patients are given higher doses. The total plasma clearance and elimination half-life of torsemide remain normal under the conditions of impaired renal function because metabolic elimination by the liver remains intact. In patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are all increased, but total clearance is unchanged. The pharmacokinetic profile of torsemide in healthy elderly subjects is similar to that in young subjects except for a decrease in renal clearance related to the decline in renal function that commonly occurs with aging. However, total plasma clearance and elimination half-life remain unchanged. Clinical Effects With oral dosing, the onset of diuresis occurs within 1 hour and the peak effect occurs during the first or second hour and diuresis lasts about 6 to 8 hours. In healthy subjects given single doses, the dose-response relationship for sodium excretion is linear over the dose range of 2.5 mg to 20 mg. The increase in potassium excretion is negligible after a single dose of up to 10 mg and only slight (5 mEq to 15 mEq) after a single dose of 20 mg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 5 Congestive Heart Failure Demadex has been studied in controlled trials in patients with New York Heart Association Class II to Class IV congestive heart failure. Patients who received 10 mg to 20 mg of daily Demadex in these studies achieved significantly greater reductions in weight and edema than did patients who received placebo. Nonanuric Renal Failure In single-dose studies in patients with nonanuric renal failure, high doses of Demadex (20 mg to 200 mg) caused marked increases in water and sodium excretion. In patients with nonanuric renal failure, severe enough to require hemodialysis, chronic treatment with up to 200 mg of daily Demadex has not been shown to change steady-state fluid retention. When patients in a study of acute renal failure received total daily doses of 520 mg to 1200 mg of Demadex, 19% experienced seizures. Ninety-six patients were treated in this study; 6/32 treated with torsemide experienced seizures, 6/32 treated with comparably high doses of furosemide experienced seizures, and 1/32 treated with placebo experienced a seizure. Hepatic Cirrhosis When given with aldosterone antagonists, Demadex also caused increases in sodium and fluid excretion in patients with edema or ascites due to hepatic cirrhosis. Urinary sodium excretion rate relative to the urinary excretion rate of Demadex is less in cirrhotic patients than in healthy subjects (possibly because of the hyperaldosteronism and resultant sodium retention that are characteristic of portal hypertension and ascites). However, because of the increased renal clearance of Demadex in patients with hepatic cirrhosis, these factors tend to balance each other, and the result is an overall natriuretic response that is similar to that seen in healthy subjects. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well- controlled trials. Essential Hypertension In patients with essential hypertension, Demadex has been shown in controlled studies to lower blood pressure when administered once a day at doses of 5 mg to 10 mg. The antihypertensive effect is near maximal after 4 to 6 weeks of treatment, but it may continue to increase for up to 12 weeks. Systolic and diastolic supine and standing blood pressures are all reduced. There is no significant orthostatic effect, and there is only a minimal peak-trough difference in blood pressure reduction. The antihypertensive effects of Demadex are, like those of other diuretics, on the average greater in black patients (a low-renin population) than in nonblack patients. When Demadex is first administered, daily urinary sodium excretion increases for at least a week. With chronic administration, however, daily sodium loss comes into balance with dietary sodium intake. If the administration of Demadex is suddenly stopped, blood pressure returns to pretreatment levels over several days, without overshoot. Demadex has been administered together with β-adrenergic blocking agents, ACE inhibitors, and calcium-channel blockers. Adverse drug interactions have not been observed, and special dosage adjustment has not been necessary. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 6 INDICATIONS AND USAGE Demadex is indicated for the treatment of edema associated with congestive heart failure, renal disease, or hepatic disease. Use of torsemide has been found to be effective for the treatment of edema associated with chronic renal failure. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials. Demadex is indicated for the treatment of hypertension alone or in combination with other antihypertensive agents. CONTRAINDICATIONS Demadex is contraindicated in patients with known hypersensitivity to Demadex or to sulfonylureas. Demadex is contraindicated in patients who are anuric. WARNINGS Hepatic Disease With Cirrhosis and Ascites Demadex should be used with caution in patients with hepatic disease with cirrhosis and ascites, since sudden alterations of fluid and electrolyte balance may precipitate hepatic coma. In these patients, diuresis with Demadex (or any other diuretic) is best initiated in the hospital. To prevent hypokalemia and metabolic alkalosis, an aldosterone antagonist or potassium-sparing drug should be used concomitantly with Demadex. Ototoxicity Tinnitus and hearing loss (usually reversible) have been observed after rapid intravenous injection of other loop diuretics and have also been observed after oral Demadex. It is not certain that these events were attributable to Demadex. Ototoxicity has also been seen in animal studies when very high plasma levels of torsemide were induced. Volume and Electrolyte Depletion Patients receiving diuretics should be observed for clinical evidence of electrolyte imbalance, hypovolemia, or prerenal azotemia. Symptoms of these disturbances may include one or more of the following: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting. Excessive diuresis may cause dehydration, blood-volume reduction, and possibly thrombosis and embolism, especially in elderly patients. In patients who develop fluid and electrolyte imbalances, hypovolemia, or prerenal azotemia, the observed laboratory changes may include hyper- or hyponatremia, hyper- or hypochloremia, hyper- or hypokalemia, acid-base abnormalities, and increased blood urea nitrogen (BUN). If any of these occur, Demadex should be discontinued until the situation is corrected; Demadex may be restarted at a lower dose. In controlled studies in the United States, Demadex was administered to hypertensive patients at doses of 5 mg or 10 mg daily. After 6 weeks at these doses, the mean decrease in serum potassium was approximately 0.1 mEq/L. The percentage of patients who had a serum This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 7 potassium level below 3.5 mEq/L at any time during the studies was essentially the same in patients who received Demadex (1.5%) as in those who received placebo (3%). In patients followed for 1 year, there was no further change in mean serum potassium levels. In patients with congestive heart failure, hepatic cirrhosis, or renal disease treated with Demadex at doses higher than those studied in United States antihypertensive trials, hypokalemia was observed with greater frequency, in a dose-related manner. In patients with cardiovascular disease, especially those receiving digitalis glycosides, diuretic- induced hypokalemia may be a risk factor for the development of arrhythmias. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH. Periodic monitoring of serum potassium and other electrolytes is advised in patients treated with Demadex. PRECAUTIONS Laboratory Values Potassium: See WARNINGS. Calcium Single doses of Demadex increased the urinary excretion of calcium by normal subjects, but serum calcium levels were slightly increased in 4- to 6-week hypertension trials. In a long-term study of patients with congestive heart failure, the average 1-year change in serum calcium was a decrease of 0.10 mg/dL (0.02 mmol/L). Among 426 patients treated with Demadex for an average of 11 months, hypocalcemia was not reported as an adverse event. Magnesium Single doses of Demadex caused healthy volunteers to increase their urinary excretion of magnesium, but serum magnesium levels were slightly increased in 4- to 6-week hypertension trials. In long-term hypertension studies, the average 1-year change in serum magnesium was an increase of 0.03 mg/dL (0.01 mmol/L). Among 426 patients treated with Demadex for an average of 11 months, one case of hypomagnesemia (1.3 mg/dL [0.53 mmol/L]) was reported as an adverse event. In a long-term clinical study of Demadex in patients with congestive heart failure, the estimated annual change in serum magnesium was an increase of 0.2 mg/dL (0.08 mmol/L), but these data are confounded by the fact that many of these patients received magnesium supplements. In a 4 week study in which magnesium supplementation was not given, the rate of occurrence of serum magnesium levels below 1.7 mg/dL (0.70 mmol/L) was 6% and 9% in the groups receiving 5 mg and 10 mg of Demadex, respectively. Blood Urea Nitrogen (BUN), Creatinine and Uric Acid Demadex produces small dose-related increases in each of these laboratory values. In hypertensive patients who received 10 mg of Demadex daily for 6 weeks, the mean increase in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 8 blood urea nitrogen was 1.8 mg/dL (0.6 mmol/L), the mean increase in serum creatinine was 0.05 mg/dL (4 mmol/L), and the mean increase in serum uric acid was 1.2 mg/dL (70 mmol/L). Little further change occurred with long-term treatment, and all changes reversed when treatment was discontinued. Symptomatic gout has been reported in patients receiving Demadex, but its incidence has been similar to that seen in patients receiving placebo. Glucose Hypertensive patients who received 10 mg of daily Demadex experienced a mean increase in serum glucose concentration of 5.5 mg/dL (0.3 mmol/L) after 6 weeks of therapy, with a further increase of 1.8 mg/dL (0.1 mmol/L) during the subsequent year. In long-term studies in diabetics, mean fasting glucose values were not significantly changed from baseline. Cases of hyperglycemia have been reported but are uncommon. Serum Lipids In the controlled short-term hypertension studies in the United States, daily doses of 5 mg, 10 mg, and 20 mg of Demadex were associated with increases in total plasma cholesterol of 4, 4, and 8 mg/dL (0.10 to 0.20 mmol/L), respectively. The changes subsided during chronic therapy. In the same short-term hypertension studies, daily doses of 5 mg, 10 mg and 20 mg of Demadex were associated with mean increases in plasma triglycerides of 16, 13 and 71 mg/dL (0.15 to 0.80 mmol/L), respectively. In long-term studies of 5 mg to 20 mg of Demadex daily, no clinically significant differences from baseline lipid values were observed after 1 year of therapy. Other In long-term studies in hypertensive patients, Demadex has been associated with small mean decreases in hemoglobin, hematocrit, and erythrocyte count and small mean increases in white blood cell count, platelet count, and serum alkaline phosphatase. Although statistically significant, all of these changes were medically inconsequential. No significant trends have been observed in any liver enzyme tests other than alkaline phosphatase. Drug Interactions In patients with essential hypertension, Demadexhas been administered together with beta- blockers, ACE inhibitors, and calcium-channel blockers. In patients with congestive heart failure, Demadex has been administered together with digitalis glycosides, ACE inhibitors, and organic nitrates. None of these combined uses was associated with new or unexpected adverse events. Torsemide does not affect the protein binding of glyburide or of warfarin, the anticoagulant effect of phenprocoumon (a related coumarin derivative), or the pharmacokinetics of digoxin or carvedilol (a vasodilator/beta-blocker). In healthy subjects, coadministration of Demadex was associated with significant reduction in the renal clearance of spironolactone, with corresponding This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 9 increases in the AUC. However, clinical experience indicates that dosage adjustment of either agent is not required. Because Demadex and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when Demadex is concomitantly administered. Also, although possible interactions between torsemide and nonsteroidal anti inflammatory agents (including aspirin) have not been studied, coadministration of these agents with another loop diuretic (furosemide) has occasionally been associated with renal dysfunction. The natriuretic effect of Demadex (like that of many other diuretics) is partially inhibited by the concomitant administration of indomethacin. This effect has been demonstrated for Demadex under conditions of dietary sodium restriction (50 mEq/day) but not in the presence of normal sodium intake (150 mEq/day). The pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine or spironolactone. Coadministration of digoxin is reported to increase the area under the curve for torsemide by 50%, but dose adjustment of Demadex is not necessary. Concomitant use of torsemide and cholestyramine has not been studied in humans but, in a study in animals, coadministration of cholestyramine decreased the absorption of orally administered torsemide. If Demadex and cholestyramine are used concomitantly, simultaneous administration is not recommended. Coadministration of probenecid reduces secretion of Demadex into the proximal tubule and thereby decreases the diuretic activity of Demadex. Other diuretics are known to reduce the renal clearance of lithium, inducing a high risk of lithium toxicity, so coadministration of lithium and diuretics should be undertaken with great caution, if at all. Coadministration of lithium and Demadex has not been studied. Other diuretics have been reported to increase the ototoxic potential of aminoglycoside antibiotics and of ethacrynic acid, especially in the presence of impaired renal function. These potential interactions with Demadex have not been studied. Carcinogenesis, Mutagenesis and Impairment of Fertility No overall increase in tumor incidence was found when torsemide was given to rats and mice throughout their lives at doses up to 9 mg/kg/day (rats) and 32 mg/kg/day (mice). On a body- weight basis, these doses are 27 to 96 times a human dose of 20 mg; on a body-surface-area basis, they are 5 to 8 times this dose. In the rat study, the high-dose female group demonstrated renal tubular injury, interstitial inflammation, and a statistically significant increase in renal adenomas and carcinomas. The tumor incidence in this group was, however, not much higher than the incidence sometimes seen in historical controls. Similar signs of chronic non-neoplastic renal injury have been reported in high-dose animal studies of other diuretics such as furosemide and hydrochlorothiazide. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 10 No mutagenic activity was detected in any of a variety of in vivo and in vitro tests of torsemide and its major human metabolite. The tests included the Ames test in bacteria (with and without metabolic activation), tests for chromosome aberrations and sister-chromatid exchanges in human lymphocytes, tests for various nuclear anomalies in cells found in hamster and murine bone marrow, tests for unscheduled DNA synthesis in mice and rats, and others. In doses up to 25 mg/kg/day (75 times a human dose of 20 mg on a body-weight basis; 13 times this dose on a body-surface-area basis), torsemide had no adverse effect on the reproductive performance of male or female rats. Pregnancy Pregnancy Category B. There was no fetotoxicity or teratogenicity in rats treated with up to 5 mg/kg/day of torsemide (on a mg/kg basis, this is 15 times a human dose of 20 mg/day; on a mg/m2 basis, the animal dose is 10 times the human dose), or in rabbits, treated with 1.6 mg/kg/day (on a mg/kg basis, 5 times the human dose of 20 mg/kg/day; on a mg/m2 basis, 1.7 times this dose). Fetal and maternal toxicity (decrease in average body weight, increase in fetal resorption and delayed fetal ossification) occurred in rabbits and rats given doses 4 (rabbits) and 5 (rats) times larger. Adequate and well-controlled studies have not been carried out in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery The effect of Demadex on labor and delivery is unknown. Nursing Mothers It is not known whether Demadex is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Demadex is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Administration of another loop diuretic to severely premature infants with edema due to patent ductus arteriosus and hyaline membrane disease has occasionally been associated with renal calcifications, sometimes barely visible on X-ray but sometimes in staghorn form, filling the renal pelves. Some of these calculi have been dissolved, and hypercalciuria has been reported to have decreased, when chlorothiazide has been coadministered along with the loop diuretic. In other premature neonates with hyaline membrane disease, another loop diuretic has been reported to increase the risk of persistent patent ductus arteriosus, possibly through a prostaglandin-E-mediated process. The use of Demadex in such patients has not been studied. Geriatric Use Of the total number of patients who received Demadex in United States clinical studies, 24% were 65 or older while about 4% were 75 or older. No specific age-related differences in effectiveness or safety were observed between younger patients and elderly patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 11 ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800 526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. At the time of approval, Demadex had been evaluated for safety in approximately 4000 subjects: over 800 of these subjects received Demadex for at least 6 months, and over 380 were treated for more than 1 year. Among these subjects were 564 who received Demadex during United States- based trials in which 274 other subjects received placebo. The reported side effects of Demadex were generally transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects occurred in 3.5% of United States patients treated with Demadex and in 4.4% of patients treated with placebo. In studies conducted in the United States and Europe, discontinuation rates due to side effects were 3.0% (38/1250) with Demadex and 3.4% (13/380) with furosemide in patients with congestive heart failure, 2.0% (8/409) with Demadex and 4.8% (11/230) with furosemide in patients with renal insufficiency, and 7.6% (13/170) with Demadex and 0% (0/33) with furosemide in patients with cirrhosis. The most common reasons for discontinuation of therapy with Demadex were (in descending order of frequency) dizziness, headache, nausea, weakness, vomiting, hyperglycemia, excessive urination, hyperuricemia, hypokalemia, excessive thirst, hypovolemia, impotence, esophageal hemorrhage, and dyspepsia. Dropout rates for these adverse events ranged from 0.1% to 0.5%. The side effects considered possibly or probably related to study drug that occurred in United States placebo-controlled trials in more than 1% of patients treated with Demadex are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 12 Table 1 Reactions Possibly or Probably Drug-Related United States Placebo-Controlled Studies Incidence (Percentages of Patients) Demadex (N=564) Placebo (N=274) Headache 7.3 9.1 Excessive Urination 6.7 2.2 Dizziness 3.2 4.0 Rhinitis 2.8 2.2 Asthenia 2.0 1.5 Diarrhea 2.0 1.1 ECG Abnormality 2.0 0.4 Cough Increase 2.0 1.5 Constipation 1.8 0.7 Nausea 1.8 0.4 Arthralgia 1.8 0.7 Dyspepsia 1.6 0.7 Sore Throat 1.6 0.7 Myalgia 1.6 1.5 Chest Pain 1.2 0.4 Insomnia 1.2 1.8 Edema 1.1 1.1 Nervousness 1.1 0.4 The daily doses of Demadex used in these trials ranged from 1.25 mg to 20 mg, with most patients receiving 5 mg to 10 mg; the duration of treatment ranged from 1 to 52 days, with a median of 41 days. Of the side effects listed in the table, only “excessive urination” occurred significantly more frequently in patients treated with Demadex than in patients treated with placebo. In the placebo-controlled hypertension studies whose design allowed side-effect rates to be attributed to dose, excessive urination was reported by 1% of patients receiving placebo, 4% of those treated with 5 mg of daily Demadex, and 15% of those treated with 10 mg. The complaint of excessive urination was generally not reported as an adverse event among patients who received Demadex for cardiac, renal, or hepatic failure. Serious adverse events reported in the clinical studies for which a drug relationship could not be excluded were atrial fibrillation, chest pain, diarrhea, digitalis intoxication, gastrointestinal hemorrhage, hyperglycemia, hyperuricemia, hypokalemia, hypotension, hypovolemia, shunt thrombosis, rash, rectal bleeding, syncope, and ventricular tachycardia. Angioedema has been reported in a patient exposed to Demadex who was later found to be allergic to sulfa drugs. Of the adverse reactions during placebo-controlled trials listed without taking into account assessment of relatedness to drug therapy, arthritis and various other nonspecific musculoskeletal problems were more frequently reported in association with Demadex than with placebo, even This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 13 though gout was somewhat more frequently associated with placebo. These reactions did not increase in frequency or severity with the dose of Demadex. One patient in the group treated with Demadex withdrew due to myalgia, and one in the placebo group withdrew due to gout. Hypokalemia: See WARNINGS. Postmarketing Experience The following adverse reactions have been identified during the post approval use of the Demadex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported include the following: leukopenia, thrombocytopenia. Serious skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported in association with torsemide use. OVERDOSAGE There is no human experience with overdoses of Demadex, but the signs and symptoms of overdosage can be anticipated to be those of excessive pharmacologic effect: dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and hemoconcentration. Treatment of overdosage should consist of fluid and electrolyte replacement. Laboratory determinations of serum levels of torsemide and its metabolites are not widely available. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of torsemide and its metabolites. Torsemide is not dialyzable, so hemodialysis will not accelerate elimination. DOSAGE AND ADMINISTRATION General Demadex tablets may be given at any time in relation to a meal, as convenient. Special dosage adjustment in the elderly is not necessary. Congestive Heart Failure The usual initial dose is 10 mg or 20 mg of once-daily oral Demadex. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied. Chronic Renal Failure The usual initial dose of Demadex is 20 mg of once-daily oral Demadex. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20136/S-023 Page 14 diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied. Hepatic Cirrhosis The usual initial dose is 5 mg or 10 mg of once-daily oral Demadex, administered together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 40 mg have not been adequately studied. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well- controlled trials. Hypertension The usual initial dose is 5 mg once daily. If the 5 mg dose does not provide adequate reduction in blood pressure within 4 to 6 weeks, the dose may be increased to 10 mg once daily. If the response to 10 mg is insufficient, an additional antihypertensive agent should be added to the treatment regimen. HOW SUPPLIED Demadex for oral administration is available as white, scored tablets containing 5 mg, 10 mg, 20 mg, or 100 mg of torsemide. The tablets are supplied in bottles of 100 as follows: Dose Shape Bottle 5 mg 10 mg 20 mg 100 mg elliptical elliptical elliptical capsule shaped NDC 0037-5005-01 NDC 0037-5010-01 NDC 0037-5020-01 NDC 0037-5001-01 Each tablet is debossed on the scored side with the logo BM and 102, 103, 104, or 105 (for 5 mg, 10 mg, 20 mg, or 100 mg, respectively). On the opposite side, the tablet is debossed with 5, 10, 20, or 100 to indicate the dose. Storage Store at 15° to 30°C (59° to 86°F). Rx only Manufactured By: Roche Farma S.A., Leganes Spain For: Meda Pharmaceuticals Meda Pharmaceuticals Inc. Somerset, NJ 08873-4120 To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800 526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.508284	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020136s023lbl.pdf', 'application_number': 20136, 'submission_type': 'SUPPL ', 'submission_number': 23}
12,244	1 2 DEMADEX 3 (torsemide) 4 TABLETS 5 IN-0455-0X Rev. 08/12 6 DESCRIPTION 7 DEMADEX (torsemide) is a diuretic of the pyridine-sulfonylurea class. Its chemical 8 name is 1-isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl] urea and its structural formula 9 is: structural formula 10 11 Its empirical formula is C16H20N4O3S, its pKa is 7.1, and its molecular weight is 348.43. 12 Torsemide is a white to off-white crystalline powder. The tablets for oral administration 13 also contain lactose NF, crospovidone NF, povidone USP, microcrystalline cellulose NF, 14 and magnesium stearate NF. 15 CLINICAL PHARMACOLOGY 16 Mechanism of Action 17 Micropuncture studies in animals have shown that torsemide acts from within the lumen 18 of the thick ascending portion of the loop of Henle, where it inhibits the Na+/K+/2CI– 19 carrier system. Clinical pharmacology studies have confirmed this site of action in 20 humans, and effects in other segments of the nephron have not been demonstrated. 21 Diuretic activity thus correlates better with the rate of drug excretion in the urine than 22 with the concentration in the blood. 23 Torsemide increases the urinary excretion of sodium, chloride, and water, but it does not 24 significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance. 25 Pharmacokinetics and Metabolism 26 The bioavailability of DEMADEX tablets is approximately 80%, with little intersubject 27 variation; the 90% confidence interval is 75% to 89%. The drug is absorbed with little 28 first-pass metabolism, and the serum concentration reaches its peak (Cmax) within 1 hour 29 after oral administration. Cmax and area under the serum concentration-time curve (AUC) 30 after oral administration are proportional to dose over the range of 2.5 mg to 200 mg. Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 Simultaneous food intake delays the time to Cmax by about 30 minutes, but overall 32 bioavailability (AUC) and diuretic activity are unchanged. Absorption is essentially 33 unaffected by renal or hepatic dysfunction. 34 The volume of distribution of torsemide is 12 liters to 15 liters in normal adults or in 35 patients with mild to moderate renal failure or congestive heart failure. In patients with 36 hepatic cirrhosis, the volume of distribution is approximately doubled. 37 In normal subjects the elimination half-life of torsemide is approximately 3.5 hours. 38 Torsemide is cleared from the circulation by both hepatic metabolism (approximately 39 80% of total clearance) and excretion into the urine (approximately 20% of total 40 clearance in patients with normal renal function). The major metabolite in humans is the 41 carboxylic acid derivative, which is biologically inactive. Two of the lesser metabolites 42 possess some diuretic activity, but for practical purposes metabolism terminates the 43 action of the drug. 44 Because torsemide is extensively bound to plasma protein (>99%), very little enters 45 tubular urine via glomerular filtration. Most renal clearance of torsemide occurs via 46 active secretion of the drug by the proximal tubules into tubular urine. 47 In patients with decompensated congestive heart failure, hepatic and renal clearance are 48 both reduced, probably because of hepatic congestion and decreased renal plasma flow, 49 respectively. The total clearance of torsemide is approximately 50% of that seen in 50 healthy volunteers, and the plasma half-life and AUC are correspondingly increased. 51 Because of reduced renal clearance, a smaller fraction of any given dose is delivered to 52 the intraluminal site of action, so at any given dose there is less natriuresis in patients 53 with congestive heart failure than in normal subjects. 54 In patients with renal failure, renal clearance of torsemide is markedly decreased but total 55 plasma clearance is not significantly altered. A smaller fraction of the administered dose 56 is delivered to the intraluminal site of action, and the natriuretic action of any given dose 57 of diuretic is reduced. A diuretic response in renal failure may still be achieved if patients 58 are given higher doses. The total plasma clearance and elimination half-life of torsemide 59 remain normal under the conditions of impaired renal function because metabolic 60 elimination by the liver remains intact. 61 In patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal 62 clearance are all increased, but total clearance is unchanged. 63 The pharmacokinetic profile of torsemide in healthy elderly subjects is similar to that in 64 young subjects except for a decrease in renal clearance related to the decline in renal 65 function that commonly occurs with aging. However, total plasma clearance and 66 elimination half-life remain unchanged. 67 Clinical Effects 68 With oral dosing, the onset of diuresis occurs within 1 hour and the peak effect occurs 69 during the first or second hour and diuresis lasts about 6 to 8 hours. In healthy subjects 70 given single doses, the dose-response relationship for sodium excretion is linear over the 71 dose range of 2.5 mg to 20 mg. The increase in potassium excretion is negligible after a Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 72 single dose of up to 10 mg and only slight (5 mEq to 15 mEq) after a single dose of 20 73 mg. 74 Congestive Heart Failure 75 DEMADEX has been studied in controlled trials in patients with New York Heart 76 Association Class II to Class IV congestive heart failure. Patients who received 10 mg to 77 20 mg of daily DEMADEX in these studies achieved significantly greater reductions in 78 weight and edema than did patients who received placebo. 79 Nonanuric Renal Failure 80 In single-dose studies in patients with nonanuric renal failure, high doses of DEMADEX 81 (20 mg to 200 mg) caused marked increases in water and sodium excretion. In patients 82 with nonanuric renal failure, severe enough to require hemodialysis, chronic treatment 83 with up to 200 mg of daily DEMADEX has not been shown to change steady-state fluid 84 retention. When patients in a study of acute renal failure received total daily doses of 520 85 mg to 1200 mg of DEMADEX, 19% experienced seizures. Ninety-six patients were 86 treated in this study; 6/32 treated with torsemide experienced seizures, 6/32 treated with 87 comparably high doses of furosemide experienced seizures, and 1/32 treated with placebo 88 experienced a seizure. 89 Hepatic Cirrhosis 90 When given with aldosterone antagonists, DEMADEX also caused increases in sodium 91 and fluid excretion in patients with edema or ascites due to hepatic cirrhosis. Urinary 92 sodium excretion rate relative to the urinary excretion rate of DEMADEX is less in 93 cirrhotic patients than in healthy subjects (possibly because of the hyperaldosteronism 94 and resultant sodium retention that are characteristic of portal hypertension and ascites). 95 However, because of the increased renal clearance of DEMADEX in patients with 96 hepatic cirrhosis, these factors tend to balance each other, and the result is an overall 97 natriuretic response that is similar to that seen in healthy subjects. Chronic use of any 98 diuretic in hepatic disease has not been studied in adequate and well-controlled trials. 99 Essential Hypertension 100 In patients with essential hypertension, DEMADEX has been shown in controlled studies 101 to lower blood pressure when administered once a day at doses of 5 mg to 10 mg. The 102 antihypertensive effect is near maximal after 4 to 6 weeks of treatment, but it may 103 continue to increase for up to 12 weeks. Systolic and diastolic supine and standing blood 104 pressures are all reduced. There is no significant orthostatic effect, and there is only a 105 minimal peak-trough difference in blood pressure reduction. 106 The antihypertensive effects of DEMADEX are, like those of other diuretics, on the 107 average greater in black patients (a low-renin population) than in nonblack patients. 108 When DEMADEX is first administered, daily urinary sodium excretion increases for at 109 least a week. With chronic administration, however, daily sodium loss comes into 110 balance with dietary sodium intake. If the administration of DEMADEX is suddenly Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 111 stopped, blood pressure returns to pretreatment levels over several days, without 112 overshoot. 113 DEMADEX has been administered together with -adrenergic blocking agents, ACE 114 inhibitors, and calcium-channel blockers. Adverse drug interactions have not been 115 observed, and special dosage adjustment has not been necessary. 116 INDICATIONS AND USAGE 117 DEMADEX is indicated for the treatment of edema associated with congestive heart 118 failure, renal disease, or hepatic disease. Use of torsemide has been found to be effective 119 for the treatment of edema associated with chronic renal failure. Chronic use of any 120 diuretic in hepatic disease has not been studied in adequate and well-controlled trials. 121 DEMADEX is indicated for the treatment of hypertension alone or in combination with 122 other antihypertensive agents. 123 CONTRAINDICATIONS 124 DEMADEX is contraindicated in patients with known hypersensitivity to DEMADEX or 125 to sulfonylureas. 126 DEMADEX is contraindicated in patients who are anuric. 127 WARNINGS 128 Hepatic Disease With Cirrhosis and Ascites 129 DEMADEX should be used with caution in patients with hepatic disease with cirrhosis 130 and ascites, since sudden alterations of fluid and electrolyte balance may precipitate 131 hepatic coma. In these patients, diuresis with DEMADEX (or any other diuretic) is best 132 initiated in the hospital. To prevent hypokalemia and metabolic alkalosis, an aldosterone 133 antagonist or potassium-sparing drug should be used concomitantly with DEMADEX. 134 Ototoxicity 135 Tinnitus and hearing loss (usually reversible) have been observed after rapid intravenous 136 injection of other loop diuretics and have also been observed after oral DEMADEX. It is 137 not certain that these events were attributable to DEMADEX. Ototoxicity has also been 138 seen in animal studies when very high plasma levels of torsemide were induced. 139 Volume and Electrolyte Depletion 140 Patients receiving diuretics should be observed for clinical evidence of electrolyte 141 imbalance, hypovolemia, or prerenal azotemia. Symptoms of these disturbances may 142 include one or more of the following: dryness of the mouth, thirst, weakness, lethargy, 143 drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, 144 tachycardia, nausea, and vomiting. Excessive diuresis may cause dehydration, blood 145 volume reduction, and possibly thrombosis and embolism, especially in elderly patients. 146 In patients who develop fluid and electrolyte imbalances, hypovolemia, or prerenal 147 azotemia, the observed laboratory changes may include hyper- or hyponatremia, hyper- 148 or hypochloremia, hyper- or hypokalemia, acid-base abnormalities, and increased blood Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 149 urea nitrogen (BUN). If any of these occur, DEMADEX should be discontinued until the 150 situation is corrected; DEMADEX may be restarted at a lower dose. 151 In controlled studies in the United States, DEMADEX was administered to hypertensive 152 patients at doses of 5 mg or 10 mg daily. After 6 weeks at these doses, the mean decrease 153 in serum potassium was approximately 0.1 mEq/L. The percentage of patients who had a 154 serum potassium level below 3.5 mEq/L at any time during the studies was essentially the 155 same in patients who received DEMADEX (1.5%) as in those who received placebo 156 (3%). In patients followed for 1 year, there was no further change in mean serum 157 potassium levels. In patients with congestive heart failure, hepatic cirrhosis, or renal 158 disease treated with DEMADEX at doses higher than those studied in United States 159 antihypertensive trials, hypokalemia was observed with greater frequency, in a dose 160 related manner. 161 In patients with cardiovascular disease, especially those receiving digitalis glycosides, 162 diuretic-induced hypokalemia may be a risk factor for the development of arrhythmias. 163 The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients 164 experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of 165 electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH. 166 Periodic monitoring of serum potassium and other electrolytes is advised in patients 167 treated with DEMADEX. 168 PRECAUTIONS 169 Laboratory Values 170 Potassium: See WARNINGS. 171 Calcium 172 Single doses of DEMADEX increased the urinary excretion of calcium by normal 173 subjects, but serum calcium levels were slightly increased in 4- to 6-week hypertension 174 trials. In a long-term study of patients with congestive heart failure, the average 1-year 175 change in serum calcium was a decrease of 0.10 mg/dL (0.02 mmol/L). Among 426 176 patients treated with DEMADEX for an average of 11 months, hypocalcemia was not 177 reported as an adverse event. 178 Magnesium 179 Single doses of DEMADEX caused healthy volunteers to increase their urinary excretion 180 of magnesium, but serum magnesium levels were slightly increased in 4- to 6-week 181 hypertension trials. In long-term hypertension studies, the average 1-year change in 182 serum magnesium was an increase of 0.03 mg/dL (0.01 mmol/L). Among 426 patients 183 treated with DEMADEX for an average of 11 months, one case of hypomagnesemia (1.3 184 mg/dL [0.53 mmol/L]) was reported as an adverse event. 185 In a long-term clinical study of DEMADEX in patients with congestive heart failure, the 186 estimated annual change in serum magnesium was an increase of 0.2 mg/dL (0.08 187 mmol/L), but these data are confounded by the fact that many of these patients received Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 188 magnesium supplements. In a 4-week study in which magnesium supplementation was 189 not given, the rate of occurrence of serum magnesium levels below 1.7 mg/dL (0.70 190 mmol/L) was 6% and 9% in the groups receiving 5 mg and 10 mg of DEMADEX, 191 respectively. 192 Blood Urea Nitrogen (BUN), Creatinine and Uric Acid 193 DEMADEX produces small dose-related increases in each of these laboratory values. In 194 hypertensive patients who received 10 mg of DEMADEX daily for 6 weeks, the mean 195 increase in blood urea nitrogen was 1.8 mg/dL (0.6 mmol/L), the mean increase in serum 196 creatinine was 0.05 mg/dL (4 mmol/L), and the mean increase in serum uric acid was 1.2 197 mg/dL (70 mmol/L). Little further change occurred with long-term treatment, and all 198 changes reversed when treatment was discontinued. 199 Symptomatic gout has been reported in patients receiving DEMADEX, but its incidence 200 has been similar to that seen in patients receiving placebo. 201 Glucose 202 Hypertensive patients who received 10 mg of daily DEMADEX experienced a mean 203 increase in serum glucose concentration of 5.5 mg/dL (0.3 mmol/L) after 6 weeks of 204 therapy, with a further increase of 1.8 mg/dL (0.1 mmol/L) during the subsequent year. In 205 long-term studies in diabetics, mean fasting glucose values were not significantly 206 changed from baseline. Cases of hyperglycemia have been reported but are uncommon. 207 Serum Lipids 208 In the controlled short-term hypertension studies in the United States, daily doses of 5 209 mg, 10 mg, and 20 mg of DEMADEX were associated with increases in total plasma 210 cholesterol of 4, 4, and 8 mg/dL (0.10 to 0.20 mmol/L), respectively. The changes 211 subsided during chronic therapy. 212 In the same short-term hypertension studies, daily doses of 5 mg, 10 mg and 20 mg of 213 DEMADEX were associated with mean increases in plasma triglycerides of 16, 13 and 214 71 mg/dL (0.15 to 0.80 mmol/L), respectively. 215 In long-term studies of 5 mg to 20 mg of DEMADEX daily, no clinically significant 216 differences from baseline lipid values were observed after 1 year of therapy. 217 Other 218 In long-term studies in hypertensive patients, DEMADEX has been associated with small 219 mean decreases in hemoglobin, hematocrit, and erythrocyte count and small mean 220 increases in white blood cell count, platelet count, and serum alkaline phosphatase. 221 Although statistically significant, all of these changes were medically inconsequential. 222 No significant trends have been observed in any liver enzyme tests other than alkaline 223 phosphatase. Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 224 Drug Interactions 225 In patients with essential hypertension, DEMADEX has been administered together with 226 beta-blockers, ACE inhibitors, and calcium-channel blockers. In patients with congestive 227 heart failure, DEMADEX has been administered together with digitalis glycosides, ACE 228 inhibitors, and organic nitrates. None of these combined uses was associated with new or 229 unexpected adverse events. 230 Torsemide does not affect the protein binding of glyburide or of warfarin, the 231 anticoagulant effect of phenprocoumon (a related coumarin derivative), or the 232 pharmacokinetics of digoxin or carvedilol (a vasodilator/beta-blocker). In healthy 233 subjects, coadministration of DEMADEX was associated with significant reduction in the 234 renal clearance of spironolactone, with corresponding increases in the AUC. However, 235 clinical experience indicates that dosage adjustment of either agent is not required. 236 Because DEMADEX and salicylates compete for secretion by renal tubules, patients 237 receiving high doses of salicylates may experience salicylate toxicity when DEMADEX 238 is concomitantly administered. Also, although possible interactions between torsemide 239 and nonsteroidal anti-inflammatory agents (including aspirin) have not been studied, 240 coadministration of these agents with another loop diuretic (furosemide) has occasionally 241 been associated with renal dysfunction. 242 The natriuretic effect of DEMADEX (like that of many other diuretics) is partially 243 inhibited by the concomitant administration of indomethacin. This effect has been 244 demonstrated for DEMADEX under conditions of dietary sodium restriction (50 245 mEq/day) but not in the presence of normal sodium intake (150 mEq/day). 246 The pharmacokinetic profile and diuretic activity of torsemide are not altered by 247 cimetidine or spironolactone. Coadministration of digoxin is reported to increase the area 248 under the curve for torsemide by 50%, but dose adjustment of DEMADEX is not 249 necessary. 250 Concomitant use of torsemide and cholestyramine has not been studied in humans but, in 251 a study in animals, coadministration of cholestyramine decreased the absorption of orally 252 administered torsemide. If DEMADEX and cholestyramine are used concomitantly, 253 simultaneous administration is not recommended. 254 Coadministration of probenecid reduces secretion of DEMADEX into the proximal 255 tubule and thereby decreases the diuretic activity of DEMADEX. 256 Other diuretics are known to reduce the renal clearance of lithium, inducing a high risk of 257 lithium toxicity, so coadministration of lithium and diuretics should be undertaken with 258 great caution, if at all. Coadministration of lithium and DEMADEX has not been studied. 259 Other diuretics have been reported to increase the ototoxic potential of aminoglycoside 260 antibiotics and of ethacrynic acid, especially in the presence of impaired renal function. 261 These potential interactions with DEMADEX have not been studied. Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 262 Carcinogenesis, Mutagenesis and Impairment of Fertility 263 No overall increase in tumor incidence was found when torsemide was given to rats and 264 mice throughout their lives at doses up to 9 mg/kg/day (rats) and 32 mg/kg/day (mice). 265 On a body-weight basis, these doses are 27 to 96 times a human dose of 20 mg; on a 266 body-surface-area basis, they are 5 to 8 times this dose. In the rat study, the high-dose 267 female group demonstrated renal tubular injury, interstitial inflammation, and a 268 statistically significant increase in renal adenomas and carcinomas. The tumor incidence 269 in this group was, however, not much higher than the incidence sometimes seen in 270 historical controls. Similar signs of chronic non-neoplastic renal injury have been 271 reported in high-dose animal studies of other diuretics such as furosemide and 272 hydrochlorothiazide. 273 No mutagenic activity was detected in any of a variety of in vivo and in vitro tests of 274 torsemide and its major human metabolite. The tests included the Ames test in bacteria 275 (with and without metabolic activation), tests for chromosome aberrations and sister 276 chromatid exchanges in human lymphocytes, tests for various nuclear anomalies in cells 277 found in hamster and murine bone marrow, tests for unscheduled DNA synthesis in mice 278 and rats, and others. 279 In doses up to 25 mg/kg/day (75 times a human dose of 20 mg on a body-weight basis; 13 280 times this dose on a body-surface-area basis), torsemide had no adverse effect on the 281 reproductive performance of male or female rats. 282 Pregnancy 283 Pregnancy Category B. 284 There was no fetotoxicity or teratogenicity in rats treated with up to 5 mg/kg/day of 285 torsemide (on a mg/kg basis, this is 15 times a human dose of 20 mg/day; on a mg/m2 286 basis, the animal dose is 10 times the human dose), or in rabbits, treated with 1.6 287 mg/kg/day (on a mg/kg basis, 5 times the human dose of 20 mg/kg/day; on a mg/m2 288 basis, 1.7 times this dose). Fetal and maternal toxicity (decrease in average body weight, 289 increase in fetal resorption and delayed fetal ossification) occurred in rabbits and rats 290 given doses 4 (rabbits) and 5 (rats) times larger. Adequate and well-controlled studies 291 have not been carried out in pregnant women. Because animal reproduction studies are 292 not always predictive of human response, this drug should be used during pregnancy only 293 if clearly needed. 294 Labor and Delivery 295 The effect of DEMADEX on labor and delivery is unknown. 296 Nursing Mothers 297 It is not known whether DEMADEX is excreted in human milk. Because many drugs are 298 excreted in human milk, caution should be exercised when DEMADEX is administered 299 to a nursing woman. Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 300 Pediatric Use 301 Safety and effectiveness in pediatric patients have not been established. 302 Administration of another loop diuretic to severely premature infants with edema due to 303 patent ductus arteriosus and hyaline membrane disease has occasionally been associated 304 with renal calcifications, sometimes barely visible on X-ray but sometimes in staghorn 305 form, filling the renal pelves. Some of these calculi have been dissolved, and 306 hypercalciuria has been reported to have decreased, when chlorothiazide has been 307 coadministered along with the loop diuretic. In other premature neonates with hyaline 308 membrane disease, another loop diuretic has been reported to increase the risk of 309 persistent patent ductus arteriosus, possibly through a prostaglandin-E-mediated process. 310 The use of DEMADEX in such patients has not been studied. 311 Geriatric Use 312 Of the total number of patients who received DEMADEX in United States clinical 313 studies, 24% were 65 or older while about 4% were 75 or older. No specific age-related 314 differences in effectiveness or safety were observed between younger patients and elderly 315 patients. 316 ADVERSE REACTIONS 317 To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals 318 Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 319 At the time of approval, DEMADEX had been evaluated for safety in approximately 320 4000 subjects: over 800 of these subjects received DEMADEX for at least 6 months, and 321 over 380 were treated for more than 1 year. Among these subjects were 564 who received 322 DEMADEX during United States-based trials in which 274 other subjects received 323 placebo. 324 The reported side effects of DEMADEX were generally transient, and there was no 325 relationship between side effects and age, sex, race, or duration of therapy. 326 Discontinuation of therapy due to side effects occurred in 3.5% of United States patients 327 treated with DEMADEX and in 4.4% of patients treated with placebo. In studies 328 conducted in the United States and Europe, discontinuation rates due to side effects were 329 3.0% (38/1250) with DEMADEX and 3.4% (13/380) with furosemide in patients with 330 congestive heart failure, 2.0% (8/409) with DEMADEX and 4.8% (11/230) with 331 furosemide in patients with renal insufficiency, and 7.6% (13/170) with DEMADEX and 332 0% (0/33) with furosemide in patients with cirrhosis. 333 The most common reasons for discontinuation of therapy with DEMADEX were (in 334 descending order of frequency) dizziness, headache, nausea, weakness, vomiting, 335 hyperglycemia, excessive urination, hyperuricemia, hypokalemia, excessive thirst, 336 hypovolemia, impotence, esophageal hemorrhage, and dyspepsia. Dropout rates for these 337 adverse events ranged from 0.1% to 0.5%. Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 338 The side effects considered possibly or probably related to study drug that occurred in 339 United States placebo-controlled trials in more than 1% of patients treated with 340 DEMADEX are shown in Table 1. 341 Table 1 Reactions Possibly or Probably Drug-Related 342 United States Placebo-Controlled Studies Incidence 343 (Percentages of Patients) DEMADEX (N=564) Placebo (N=274) Headache 7.3 9.1 Excessive Urination 6.7 2.2 Dizziness 3.2 4.0 Rhinitis 2.8 2.2 Asthenia 2.0 1.5 Diarrhea 2.0 1.1 ECG Abnormality 2.0 0.4 Cough Increase 2.0 1.5 Constipation 1.8 0.7 Nausea 1.8 0.4 Arthralgia 1.8 0.7 Dyspepsia 1.6 0.7 Sore Throat 1.6 0.7 Myalgia 1.6 1.5 Chest Pain 1.2 0.4 Insomnia 1.2 1.8 Edema 1.1 1.1 Nervousness 1.1 0.4 344 The daily doses of DEMADEX used in these trials ranged from 1.25 mg to 20 mg, with 345 most patients receiving 5 mg to 10 mg; the duration of treatment ranged from 1 to 52 346 days, with a median of 41 days. Of the side effects listed in the table, only “excessive 347 urination” occurred significantly more frequently in patients treated with DEMADEX 348 than in patients treated with placebo. In the placebo-controlled hypertension studies 349 whose design allowed side-effect rates to be attributed to dose, excessive urination was 350 reported by 1% of patients receiving placebo, 4% of those treated with 5 mg of daily 351 DEMADEX, and 15% of those treated with 10 mg. The complaint of excessive urination 352 was generally not reported as an adverse event among patients who received DEMADEX 353 for cardiac, renal, or hepatic failure. 354 Serious adverse events reported in the clinical studies for which a drug relationship could 355 not be excluded were atrial fibrillation, chest pain, diarrhea, digitalis intoxication, 356 gastrointestinal hemorrhage, hyperglycemia, hyperuricemia, hypokalemia, hypotension, 357 hypovolemia, shunt thrombosis, rash, rectal bleeding, syncope, and ventricular 358 tachycardia. 359 Angioedema has been reported in a patient exposed to DEMADEX who was later found 360 to be allergic to sulfa drugs. Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 361 Of the adverse reactions during placebo-controlled trials listed without taking into 362 account assessment of relatedness to drug therapy, arthritis and various other nonspecific 363 musculoskeletal problems were more frequently reported in association with DEMADEX 364 than with placebo, even though gout was somewhat more frequently associated with 365 placebo. These reactions did not increase in frequency or severity with the dose of 366 DEMADEX. One patient in the group treated with DEMADEX withdrew due to myalgia, 367 and one in the placebo group withdrew due to gout. 368 Hypokalemia: See WARNINGS. 369 Postmarketing Experience 370 The following adverse reactions have been identified during the post approval use of 371 Demadex. Because these reactions are reported voluntarily from a population of 372 uncertain size, it is not always possible to reliably estimate their frequency or establish a 373 causal relationship to drug exposure. Adverse reactions reported include the following: 374 leucopenia, thrombocytopenia. 375 Serious skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis) have 376 been reported in association with torsemide use. 377 Pancreatitis has been reported in association with torsemide use. 378 379 OVERDOSAGE 380 There is no human experience with overdoses of DEMADEX, but the signs and 381 symptoms of overdosage can be anticipated to be those of excessive pharmacologic 382 effect: dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, 383 hypochloremic alkalosis, and hemoconcentration. Treatment of overdosage should 384 consist of fluid and electrolyte replacement. 385 Laboratory determinations of serum levels of torsemide and its metabolites are not widely 386 available. 387 No data are available to suggest physiological maneuvers (e.g., maneuvers to change the 388 pH of the urine) that might accelerate elimination of torsemide and its metabolites. 389 Torsemide is not dialyzable, so hemodialysis will not accelerate elimination. 390 DOSAGE AND ADMINISTRATION 391 General 392 DEMADEX tablets may be given at any time in relation to a meal, as convenient. Special 393 dosage adjustment in the elderly is not necessary. 394 Congestive Heart Failure 395 The usual initial dose is 10 mg or 20 mg of once-daily oral DEMADEX. If the diuretic 396 response is inadequate, the dose should be titrated upward by approximately doubling Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 397 until the desired diuretic response is obtained. Single doses higher than 200 mg have not 398 been adequately studied. 399 Chronic Renal Failure 400 The usual initial dose of DEMADEX is 20 mg of once-daily oral DEMADEX. If the 401 diuretic response is inadequate, the dose should be titrated upward by approximately 402 doubling until the desired diuretic response is obtained. Single doses higher than 200 mg 403 have not been adequately studied. 404 Hepatic Cirrhosis 405 The usual initial dose is 5 mg or 10 mg of once-daily oral DEMADEX, administered 406 together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic 407 response is inadequate, the dose should be titrated upward by approximately doubling 408 until the desired diuretic response is obtained. Single doses higher than 40 mg have not 409 been adequately studied. 410 Chronic use of any diuretic in hepatic disease has not been studied in adequate and well 411 controlled trials. 412 Hypertension 413 The usual initial dose is 5 mg once daily. If the 5 mg dose does not provide adequate 414 reduction in blood pressure within 4 to 6 weeks, the dose may be increased to 10 mg once 415 daily. If the response to 10 mg is insufficient, an additional antihypertensive agent should 416 be added to the treatment regimen. 417 HOW SUPPLIED 418 DEMADEX for oral administration is available as white, scored tablets containing 5 mg, 419 10 mg, 20 mg, or 100 mg of torsemide. The tablets are supplied in bottles of 100 as 420 follows: Dose Shape Bottle 5 mg elliptical NDC 0037-5005-01 10 mg elliptical NDC 0037-5010-01 20 mg elliptical NDC 0037-5020-01 100 mg capsule shaped NDC 0037-5001-01 421 Each tablet is debossed on the scored side with the logo BM and 102, 103, 104, or 105 422 (for 5 mg, 10 mg, 20 mg, or 100 mg, respectively). On the opposite side, the tablet is 423 debossed with 5, 10, 20, or 100 to indicate the dose. 424 Storage 425 Store at 15° to 30°C (59° to 86°F). 426 Rx Only 427 Manufactured By: Roche Farma S.A., Leganes, Spain 428 For: Meda Pharmaceuticals Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 429 Meda Pharmaceuticals Inc. 430 Somerset, NJ 08873-4120 431 432 To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals 433 Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 434 435 Printed in USA 436 © 2012 Meda Pharmaceuticals Inc. 437 IN-0455-0X Rev. 08/12 438 Reference ID: 3174186 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.804723	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020136s014lbl.pdf', 'application_number': 20136, 'submission_type': 'SUPPL ', 'submission_number': 24}
12,245	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Levoleucovorin safely and effectively. See full prescribing information for Levoleucovorin. Levoleucovorin (for Injection) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION for INTRAVENOUS use Initial U.S. Approval: 1952 (d,l-leucovorin), 2008 (levoleucovorin) --------------------INDICATIONS AND USAGE-------------------- Levoleucovorin is a folate analog. (1) Levoleucovorin rescue is indicated after high-dose methotrexate therapy in osteosarcoma. (1) Levoleucovorin is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. (1) Limitations of Use Levoleucovorin is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. (1.1) --------------------DOSAGE AND ADMINISTRATION-------------------- Levoleucovorin Rescue After High-Dose Methotrexate Therapy Do not administer intrathecally. (2.1) Levoleucovorin is dosed at one-half the usual dose of the racemic form. (2.1) Levoleucovorin rescue recommendations are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours. Levoleucovorin rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Determine serum creatinine and methotrexate levels at least once daily. Continue levoleucovorin administration, hydration, and urinary alkalinization (pH of 7.0 or greater) until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The levoleucovorin dose may need to be adjusted. (2.3) --------------------DOSAGE FORMS AND STRENGTHS-------------------- Each 50 mg single-use vial of Levoleucovorin for Injection contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin ) and 50 mg mannitol. (16) It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride for Injection, USP. (2.5, 11) --------------------CONTRAINDICATIONS-------------------- Levoleucovorin is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. (4) --------------------WARNINGS AND PRECAUTIONS-------------------- Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. (5.1) Levoleucovorin enhances the toxicity of fluorouracil. (5.2,7) Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study. (5.3) --------------------ADVERSE REACTIONS-------------------- Allergic reactions were reported in patients receiving levoleucovorin. (6.2) Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving levoleucovorin as rescue after high dose methotrexate therapy. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Spectrum Pharmaceuticals, Inc. at 1-866-473-4936 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch --------------------DRUG INTERACTIONS-------------------- Levoleucovorin may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients. (7) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Administration Guidelines 2.2 Co-administration of levoleucovorin with other agents 2.3 Levoleucovorin Rescue After High-Dose Methotrexate Therapy 2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage 2.5 Reconstitution and Infusion Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Rate of Administration 5.2 Potential for Enhanced Toxicity with 5-Fluorouracil 5.3 Potential for interaction with trimethoprim-sulfamethoxazole 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility 13.2 Animal Toxicology And/Or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING *Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE • Levoleucovorin is a folate analog. • Levoleucovorin rescue is indicated after high-dose methotrexate therapy in osteosarcoma. • Levoleucovorin is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. 1.1 Limitations of Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Levoleucovorin is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. 2 DOSAGE AND ADMINISTRATION 2.1 Administration Guidelines Levoleucovorin is dosed at one-half the usual dose of the racemic form. Levoleucovorin is indicated for intravenous administration only. Do not administer intrathecally. 2.2 Co-administration of levoleucovorin with other agents Due to the risk of precipitation, do not co-administer levoleucovorin with other agents in the same admixture. 2.3 Levoleucovorin Rescue After High-Dose Methotrexate Therapy The recommendations for levoleucovorin rescue are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). Levoleucovorin rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Serum creatinine and methotrexate levels should be determined at least once daily. Levoleucovorin administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The levoleucovorin dose should be adjusted or rescue extended based on the following guidelines. Table 1 Guidelines for Levoleucovorin Dosage and Administration Clinical Situation Laboratory Findings Levoleucovorin Dosage and Duration Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours 7.5 mg IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 7.5 mg IV q 6 hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate levoleucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda levoleucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed. Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of levoleucovorin or prolonged administration may be indicated. Although levoleucovorin may ameliorate the hematologic toxicity associated with high dose methotrexate, levoleucovorin has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney. 2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage Levoleucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and levoleucovorin rescue increases, levoleucovorin’s effectiveness in counteracting toxicity may decrease. Levoleucovorin 7.5 mg (approximately 5 mg/m2 ) should be administered IV every 6 hours until the serum methotrexate level is less than 10-8 M. Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of levoleucovorin should be increased to 50 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater. 2.5 Reconstitution and Infusion Instructions • Prior to intravenous injection, the 50 mg vial of Levoleucovorin for Injection is reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives (e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended. • The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. • Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or further dilution using 0.9% Sodium Chloride Injection, USP may be held at room temperature for not more than a total of 12 hours. Dilutions in 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours. • Visually inspect the reconstituted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed. • No more than 16 mL of reconstituted solutions (160 mg of levoleucovorin ) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution. 3 DOSAGE FORMS AND STRENGTHS Levoleucovorin for Injection is supplied in sterile, single-use vials containing 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin ) and 50 mg mannitol. 4 CONTRAINDICATIONS Levoleucovorin is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. 5 WARNINGS AND PRECAUTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.1 Rate of Administration Because of the Ca++ content of the levoleucovorin solution, no more than 16 mL (160 mg of levoleucovorin ) should be injected intravenously per minute. 5.2 Potential for Enhanced Toxicity with 5-Fluorouracil Levoleucovorin enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. 5.3 Potential for interaction with trimethoprim-sulfamethoxazole The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Since clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following table presents the frequency of adverse reactions which occurred during the administration of 58 courses of high dose methotrexate 12 grams/m2 followed by levoleucovorin rescue for osteosarcoma in 16 patients age 6- 21. Most patients received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Table 2 Adverse Reactions Body System/Adverse Reactions Number (%) of Patients with Adverse Reactions Number (%) of Courses with Adverse Reactions (N =16) (N = 58) All Grade 3+ All Grade 3+ Gastrointestinal Stomatitis 6 (37.5) 1 (6.3) 10 (17.2) 1 (1.7) Vomiting 6 (37.5) 0 14 (24.1) 0 Nausea 3 (18.8) 0 3 (5.2) 0 Diarrhea 1 (6.3) 0 1 (1.7) 0 Dyspepsia 1 (6.3) 0 1 (1.7) 0 Typhlitis 1 (6.3) 1 (6.3) 1 (1.7) 1 (1.7) Respiratory Dyspnea 1 (6.3) 0 1 (1.7) 0 Skin and Appendages Dermatitis 1 (6.3) 0 1 (1.7) 0 Other Confusion 1 (6.3) 0 1 (1.7) 0 Neuropathy 1 (6.3) 0 1 (1.7) 0 Renal function abnormal 1 (6.3) 0 3 (5.2) 0 Taste perversion 1 (6.3) 0 1 (1.7) 0 Total number of patients 9 (56.3) 2 (12.5) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Total number of courses 25 (43.1) 2 (3.4) The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high dose methotrexate with levoleucovorin rescue because patients were receiving other myelosuppressive chemotherapy. 6.2 Postmarketing Experience Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reaction.” 7 DRUG INTERACTIONS Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects. However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs. Preliminary human studies have shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. Levoleucovorin increases the toxicity of 5-fluorouracil [see Warnings and Precautions (5.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. It is not known whether levoleucovorin can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when levoleucovorin is administered to a nursing mother. 8.4 Pediatric Use [See Clinical Studies (14)] 8.5 Geriatric Use Clinical studies of levoleucovorin in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. 10 OVERDOSAGE No data are available for overdosage with levoleucovorin. 11 DESCRIPTION Levoleucovorin is the levo isomeric form of racemic d,l-leucovorin, present as the calcium salt. Levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin]. Levoleucovorin for injection contains levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by methotrexate. This This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda compound has the chemical designation calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6- pteridinyl)methyl] amino]benzoyl-L-glutamate pentahydrate. The molecular weight is 601.6 and the structural formula is: Its molecular formula is: C20H21CaN7O7 . 5 H2O. Levoleucovorin for injection is supplied as a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol per 50 mg vial. Sodium hydroxide and/or hydrocholoric acid are used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride Injection, USP [See Dosage and Administration (2.5)] 12 CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one- carbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. 12.2 Pharmacodynamics Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5- methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5- methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate. 12.3 Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8- tetrahydrofolate was 5.1 and 6.8 hours, respectively. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13.2 Animal Toxicology And/Or Pharmacology The acute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m2) and 378 mg/kg ( 2268 mg/m2), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m2, which represents a 3-log safety margin. 14 CLINICAL STUDIES The safety and efficacy of levoleucovorin rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m2 IV over 4 hours was administered to 13 patients, who received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m2 IV over 6 hours, followed by levoleucovorin 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of levoleucovorin doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of levoleucovorin rescue following high-dose methotrexate was based on the adverse reaction profile. [See Adverse Reactions (6)] 16 HOW SUPPLIED/STORAGE AND HANDLING Each 50 mg single-use vial of Levoleucovorin for Injection contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol. 50 mg vial of freeze-dried powder – NDC 68152-101-00. Store at 25° C (77 °F) in carton until contents are used. Excursions permitted from 15-30° C (59-86 °F). [See USP Controlled Room Temperature]. Protect from light. Manufactured for Spectrum Pharmaceuticals, Inc. Irvine, CA 92618 Manufactured by Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230 Spectrum Pharmaceuticals, Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.854324	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020140lbl.pdf', 'application_number': 20140, 'submission_type': 'ORIG ', 'submission_number': 1}
12,242	1 PRESCRIBING INFORMATION 2 IMITREX® 3 (sumatriptan succinate) 4 Tablets 5 DESCRIPTION 6 IMITREX Tablets contain sumatriptan (as the succinate), a selective 5-hydroxytryptamine1 7 receptor subtype agonist. Sumatriptan succinate is chemically designated as 3-[2 8 (dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the 9 following structure: 10 structural formula 11 12 13 The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5. 14 Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in 15 saline. Each IMITREX Tablet for oral administration contains 35, 70, or 140 mg of sumatriptan 16 succinate equivalent to 25, 50, or 100 mg of sumatriptan, respectively. Each tablet also contains 17 the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, 18 microcrystalline cellulose, and sodium bicarbonate. Each 100-mg tablet also contains 19 hypromellose, iron oxide, titanium dioxide, and triacetin. 20 CLINICAL PHARMACOLOGY 21 Mechanism of Action: Sumatriptan is an agonist for a vascular 5-hydroxytryptamine1 22 receptor subtype (probably a member of the 5-HT1D family) having only a weak affinity for 23 5-HT1A, 5-HT5A, and 5-HT7 receptors and no significant affinity (as measured using standard 24 radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, or 5-HT4 receptor 25 subtypes or at alpha1-, alpha2-, or beta-adrenergic; dopamine1; dopamine2; muscarinic; or 26 benzodiazepine receptors. 27 The vascular 5-HT1 receptor subtype that sumatriptan activates is present on cranial arteries in 28 both dog and primate, on the human basilar artery, and in the vasculature of human dura mater 29 and mediates vasoconstriction. This action in humans correlates with the relief of migraine 30 headache. In addition to causing vasoconstriction, experimental data from animal studies show 31 that sumatriptan also activates 5-HT1 receptors on peripheral terminals of the trigeminal nerve 32 innervating cranial blood vessels. Such an action may also contribute to the antimigrainous effect 33 of sumatriptan in humans. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with 35 little or no effect on arterial blood pressure or total peripheral resistance. In the cat, sumatriptan 36 selectively constricts the carotid arteriovenous anastomoses while having little effect on blood 37 flow or resistance in cerebral or extracerebral tissues. 38 Pharmacokinetics: The mean maximum concentration following oral dosing with 25 mg is 39 18 ng/mL (range, 7 to 47 ng/mL) and 51 ng/mL (range, 28 to 100 ng/mL) following oral dosing 40 with 100 mg of sumatriptan. This compares with a Cmax of 5 and 16 ng/mL following dosing 41 with a 5- and 20-mg intranasal dose, respectively. The mean Cmax following a 6-mg 42 subcutaneous injection is 71 ng/mL (range, 49 to 110 ng/mL). The bioavailability is 43 approximately 15%, primarily due to presystemic metabolism and partly due to incomplete 44 absorption. The Cmax is similar during a migraine attack and during a migraine-free period, but 45 the Tmax is slightly later during the attack, approximately 2.5 hours compared to 2.0 hours. When 46 given as a single dose, sumatriptan displays dose proportionality in its extent of absorption (area 47 under the curve [AUC]) over the dose range of 25 to 200 mg, but the Cmax after 100 mg is 48 approximately 25% less than expected (based on the 25-mg dose). 49 A food effect study involving administration of IMITREX Tablets 100 mg to healthy 50 volunteers under fasting conditions and with a high-fat meal indicated that the Cmax and AUC 51 were increased by 15% and 12%, respectively, when administered in the fed state. 52 Plasma protein binding is low (14% to 21%). The effect of sumatriptan on the protein binding 53 of other drugs has not been evaluated, but would be expected to be minor, given the low rate of 54 protein binding. The apparent volume of distribution is 2.4 L/kg. 55 The elimination half-life of sumatriptan is approximately 2.5 hours. Radiolabeled 56 14C-sumatriptan administered orally is largely renally excreted (about 60%) with about 40% 57 found in the feces. Most of the radiolabeled compound excreted in the urine is the major 58 metabolite, indole acetic acid (IAA), which is inactive, or the IAA glucuronide. Only 3% of the 59 dose can be recovered as unchanged sumatriptan. 60 In vitro studies with human microsomes suggest that sumatriptan is metabolized by 61 monoamine oxidase (MAO), predominantly the A isoenzyme, and inhibitors of that enzyme may 62 alter sumatriptan pharmacokinetics to increase systemic exposure. No significant effect was seen 63 with an MAO-B inhibitor (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: 64 Drug Interactions). 65 Special Populations: Renal Impairment: The effect of renal impairment on the 66 pharmacokinetics of sumatriptan has not been examined, but little clinical effect would be 67 expected as sumatriptan is largely metabolized to an inactive substance. 68 Hepatic Impairment: The liver plays an important role in the presystemic clearance of 69 orally administered sumatriptan. Accordingly, the bioavailability of sumatriptan following oral 70 administration may be markedly increased in patients with liver disease. In 1 small study of 71 hepatically impaired patients (N = 8) matched for sex, age, and weight with healthy subjects, the 72 hepatically impaired patients had an approximately 70% increase in AUC and Cmax and a Tmax 73 40 minutes earlier compared to the healthy subjects (see DOSAGE AND ADMINISTRATION). 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 74 Age: The pharmacokinetics of oral sumatriptan in the elderly (mean age, 72 years; 2 males 75 and 4 females) and in patients with migraine (mean age, 38 years; 25 males and 155 females) 76 were similar to that in healthy male subjects (mean age, 30 years) (see PRECAUTIONS: 77 Geriatric Use). 78 Gender: In a study comparing females to males, no pharmacokinetic differences were 79 observed between genders for AUC, Cmax, Tmax, and half-life. 80 Race: The systemic clearance and Cmax of sumatriptan were similar in black (N = 34) and 81 Caucasian (N = 38) healthy male subjects. 82 Drug Interactions: Monoamine Oxidase Inhibitors: Treatment with MAO-A inhibitors 83 generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and 84 PRECAUTIONS). 85 Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after 86 coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after 87 coadministration of the monoamine oxidase inhibitors (MAOI) with subcutaneous sumatriptan. 88 In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance 89 of subcutaneous sumatriptan. Under the conditions of this experiment, the result was a 2-fold 90 increase in the area under the sumatriptan plasma concentration x time curve (AUC), 91 corresponding to a 40% increase in elimination half-life. This interaction was not evident with an 92 MAO-B inhibitor. 93 A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the 94 bioavailability from a 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase 95 in systemic exposure. 96 Alcohol: Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the 97 pharmacokinetics of sumatriptan. 98 CLINICAL STUDIES 99 The efficacy of IMITREX Tablets in the acute treatment of migraine headaches was 100 demonstrated in 3, randomized, double-blind, placebo-controlled studies. Patients enrolled in 101 these 3 studies were predominately female (87%) and Caucasian (97%), with a mean age of 102 40 years (range, 18 to 65 years). Patients were instructed to treat a moderate to severe headache. 103 Headache response, defined as a reduction in headache severity from moderate or severe pain to 104 mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, 105 photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up 106 to 24 hours postdose. A second dose of IMITREX Tablets or other medication was allowed 4 to 107 24 hours after the initial treatment for recurrent headache. Acetaminophen was offered to 108 patients in Studies 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not 109 improved or worsened. Additional medications were allowed 4 to 24 hours after the initial 110 treatment for recurrent headache or as rescue in all 3 studies. The frequency and time to use of 111 these additional treatments were also determined. In all studies, doses of 25, 50, and 100 mg 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 112 were compared to placebo in the treatment of migraine attacks. In 1 study, doses of 25, 50, and 113 100 mg were also compared to each other. 114 In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after 115 treatment was significantly greater among patients receiving IMITREX Tablets at all doses 116 compared to those who received placebo. In 1 of the 3 studies, there was a statistically significant 117 greater percentage of patients with headache response at 2 and 4 hours in the 50- or 100-mg 118 group when compared to the 25-mg dose groups. There were no statistically significant 119 differences between the 50- and 100-mg dose groups in any study. The results from the 3 120 controlled clinical trials are summarized in Table 1. 121 Comparisons of drug performance based upon results obtained in different clinical trials 122 are never reliable. Because studies are conducted at different times, with different samples 123 of patients, by different investigators, employing different criteria and/or different 124 interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), 125 quantitative estimates of treatment response and the timing of response may be expected to 126 vary considerably from study to study. 127 128 Table 1. Percentage of Patients With Headache Response (No or Mild Pain) 2 and 4 Hours 129 Following Treatment Placebo 2 hr 4 hr IMITREX Tablets 25 mg 2 hr 4 hr IMITREX Tablets 50 mg 2 hr 4 hr IMITREX Tablets 100 mg 2 hr 4 hr Study 1 27% 38% (N = 94) 52%* 67%* (N = 298) 61%† 78%† (N = 296) 62%† 79%† (N = 296) Study 2 26% 38% (N = 65) 52%* 70%* (N = 66) 50%* 68%* (N = 62) 56%* 71%* (N = 66) Study 3 17% 19% (N = 47) 52%* 65%* (N = 48) 54%* 72%* (N = 46) 57%* 78%* (N = 46) 130 p<0.05 in comparison with placebo. 131 †p<0.05 in comparison with 25 mg. 132 133 The estimated probability of achieving an initial headache response over the 4 hours following 134 treatment is depicted in Figure 1. 135 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 136 Figure 1. Estimated Probability of Achieving Initial Headache Response Within 137 240 Minutes 138 graph 140 141 * The figure shows the probability over time of obtaining headache response (no or mild pain) 142 following treatment with sumatriptan. The averages displayed are based on pooled data from 143 the 3 clinical controlled trials providing evidence of efficacy. Kaplan-Meier plot with patients 144 not achieving response and/or taking rescue within 240 minutes censored to 240 minutes. 145 146 For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, 147 there was a lower incidence of these symptoms at 2 hours (Study 1) and at 4 hours (Studies 1, 2, 148 and 3) following administration of IMITREX Tablets compared to placebo. 149 As early as 2 hours in Studies 2 and 3 or 4 hours in Study 1, through 24 hours following the 150 initial dose of study treatment, patients were allowed to use additional treatment for pain relief in 151 the form of a second dose of study treatment or other medication. The estimated probability of 152 patients taking a second dose or other medication for migraine over the 24 hours following the 153 initial dose of study treatment is summarized in Figure 2. 154 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 155 Figure 2. The Estimated Probability of Patients Taking a Second Dose or Other 156 Medication for Migraine Over the 24 Hours Following the Initial Dose of Study 157 Treatment* 158 graph 160 161 * Kaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence 162 of efficacy with patients not using additional treatments censored to 24 hours. Plot also 163 includes patients who had no response to the initial dose. No remedication was allowed within 164 2 hours postdose. 165 166 There is evidence that doses above 50 mg do not provide a greater effect than 50 mg. There 167 was no evidence to suggest that treatment with sumatriptan was associated with an increase in 168 the severity of recurrent headaches. The efficacy of IMITREX Tablets was unaffected by 169 presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient; 170 relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., 171 beta-blockers, calcium channel blockers, tricyclic antidepressants). There were insufficient data 172 to assess the impact of race on efficacy. 173 INDICATIONS AND USAGE 174 IMITREX Tablets are indicated for the acute treatment of migraine attacks with or without 175 aura in adults. 176 IMITREX Tablets are not intended for the prophylactic therapy of migraine or for use in the 177 management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and 178 effectiveness of IMITREX Tablets have not been established for cluster headache, which is 179 present in an older, predominantly male population. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 180 CONTRAINDICATIONS 181 IMITREX Tablets should not be given to patients with history, symptoms, or signs of 182 ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. In addition, patients 183 with other significant underlying cardiovascular diseases should not receive IMITREX 184 Tablets. Ischemic cardiac syndromes include, but are not limited to, angina pectoris of any 185 type (e.g., stable angina of effort and vasospastic forms of angina such as the Prinzmetal 186 variant), all forms of myocardial infarction, and silent myocardial ischemia. 187 Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as 188 transient ischemic attacks. Peripheral vascular disease includes, but is not limited to, 189 ischemic bowel disease (see WARNINGS). 190 Because IMITREX Tablets may increase blood pressure, they should not be given to 191 patients with uncontrolled hypertension. 192 Concurrent administration of MAO-A inhibitors or use within 2 weeks of 193 discontinuation of MAO-A inhibitor therapy is contraindicated (see CLINICAL 194 PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions). 195 IMITREX Tablets should not be administered to patients with hemiplegic or basilar 196 migraine. 197 IMITREX Tablets and any ergotamine-containing or ergot-type medication (like 198 dihydroergotamine or methysergide) should not be used within 24 hours of each other, nor 199 should IMITREX and another 5-HT1 agonist. 200 IMITREX Tablets are contraindicated in patients with hypersensitivity to sumatriptan 201 or any of their components. 202 IMITREX Tablets are contraindicated in patients with severe hepatic impairment. 203 WARNINGS 204 IMITREX Tablets should only be used where a clear diagnosis of migraine headache has 205 been established. 206 Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: 207 Sumatriptan should not be given to patients with documented ischemic or vasospastic 208 coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended 209 that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the 210 presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, 211 diabetes, strong family history of CAD, female with surgical or physiological menopause, 212 or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory 213 clinical evidence that the patient is reasonably free of coronary artery and ischemic 214 myocardial disease or other significant underlying cardiovascular disease. The sensitivity 215 of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to 216 coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the 217 patient’s medical history or electrocardiographic investigations reveal findings indicative 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 218 of, or consistent with, coronary artery vasospasm or myocardial ischemia, sumatriptan 219 should not be administered (see CONTRAINDICATIONS). 220 For patients with risk factors predictive of CAD, who are determined to have a 221 satisfactory cardiovascular evaluation, it is strongly recommended that administration of 222 the first dose of sumatriptan tablets take place in the setting of a physician’s office or 223 similar medically staffed and equipped facility unless the patient has previously received 224 sumatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, 225 consideration should be given to obtaining on the first occasion of use an electrocardiogram 226 (ECG) during the interval immediately following IMITREX Tablets, in these patients with 227 risk factors. 228 It is recommended that patients who are intermittent long-term users of sumatriptan 229 and who have or acquire risk factors predictive of CAD, as described above, undergo 230 periodic interval cardiovascular evaluation as they continue to use sumatriptan. 231 The systematic approach described above is intended to reduce the likelihood that 232 patients with unrecognized cardiovascular disease will be inadvertently exposed to 233 sumatriptan. 234 Drug-Associated Cardiac Events and Fatalities: Serious adverse cardiac events, 235 including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death 236 have been reported within a few hours following the administration of IMITREX® (sumatriptan 237 succinate) Injection or IMITREX Tablets. Considering the extent of use of sumatriptan in 238 patients with migraine, the incidence of these events is extremely low. 239 The fact that sumatriptan can cause coronary vasospasm, that some of these events have 240 occurred in patients with no prior cardiac disease history and with documented absence of CAD, 241 and the close proximity of the events to sumatriptan use support the conclusion that some of 242 these cases were caused by the drug. In many cases, however, where there has been known 243 underlying coronary artery disease, the relationship is uncertain. 244 Premarketing Experience With Sumatriptan: Of 6,348 patients with migraine who 245 participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan, 2 246 experienced clinical adverse events shortly after receiving oral sumatriptan that may have 247 reflected coronary vasospasm. Neither of these adverse events was associated with a serious 248 clinical outcome. 249 Among the more than 1,900 patients with migraine who participated in premarketing 250 controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained 251 clinical events during or shortly after receiving sumatriptan that may have reflected coronary 252 artery vasospasm. Six of these 8 patients had ECG changes consistent with transient ischemia, 253 but without accompanying clinical symptoms or signs. Of these 8 patients, 4 had either findings 254 suggestive of CAD or risk factors predictive of CAD prior to study enrollment. 255 Among approximately 4,000 patients with migraine who participated in premarketing 256 controlled and uncontrolled clinical trials of sumatriptan nasal spray, 1 patient experienced an 257 asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event. 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 258 Postmarketing Experience With Sumatriptan: Serious cardiovascular events, some 259 resulting in death, have been reported in association with the use of IMITREX Injection or 260 IMITREX Tablets. The uncontrolled nature of postmarketing surveillance, however, makes it 261 impossible to determine definitively the proportion of the reported cases that were actually 262 caused by sumatriptan or to reliably assess causation in individual cases. On clinical grounds, the 263 longer the latency between the administration of IMITREX and the onset of the clinical event, 264 the less likely the association is to be causative. Accordingly, interest has focused on events 265 beginning within 1 hour of the administration of IMITREX. 266 Cardiac events that have been observed to have onset within 1 hour of sumatriptan 267 administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, 268 ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death. 269 Some of these events occurred in patients who had no findings of CAD and appear to 270 represent consequences of coronary artery vasospasm. However, among domestic reports of 271 serious cardiac events within 1 hour of sumatriptan administration, almost all of the patients had 272 risk factors predictive of CAD and the presence of significant underlying CAD was established 273 in most cases (see CONTRAINDICATIONS). 274 Drug-Associated Cerebrovascular Events and Fatalities: Cerebral hemorrhage, 275 subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in 276 patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The 277 relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible 278 that the cerebrovascular events were primary, sumatriptan having been administered in the 279 incorrect belief that the symptoms experienced were a consequence of migraine when they were 280 not. As with other acute migraine therapies, before treating headaches in patients not previously 281 diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should 282 be taken to exclude other potentially serious neurological conditions. It should also be noted that 283 patients with migraine may be at increased risk of certain cerebrovascular events (e.g., 284 cerebrovascular accident, transient ischemic attack). 285 Other Vasospasm-Related Events: Sumatriptan may cause vasospastic reactions other than 286 coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with 287 abdominal pain and bloody diarrhea have been reported. Very rare reports of transient and 288 permanent blindness and significant partial vision loss have been reported with the use of 289 sumatriptan. Visual disorders may also be part of a migraine attack. 290 Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome 291 may occur with triptans, including treatment with IMITREX, particularly during combined use 292 with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake 293 inhibitors (SNRIs). If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, 294 paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, 295 duloxetine) is clinically warranted, careful observation of the patient is advised, particularly 296 during treatment initiation and dose increases. Serotonin syndrome symptoms may include 297 mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 298 tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, 299 incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). 300 Increase in Blood Pressure: Significant elevation in blood pressure, including hypertensive 301 crisis, has been reported on rare occasions in patients with and without a history of hypertension. 302 Sumatriptan is contraindicated in patients with uncontrolled hypertension (see 303 CONTRAINDICATIONS). Sumatriptan should be administered with caution to patients with 304 controlled hypertension as transient increases in blood pressure and peripheral vascular resistance 305 have been observed in a small proportion of patients. 306 Concomitant Drug Use: In patients taking MAO-A inhibitors, sumatriptan plasma levels 307 attained after treatment with recommended doses are 7-fold higher following oral administration 308 than those obtained under other conditions. Accordingly, the coadministration of IMITREX 309 Tablets and an MAO-A inhibitor is contraindicated (see CLINICAL PHARMACOLOGY and 310 CONTRAINDICATIONS). 311 Hypersensitivity: Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on 312 rare occasions in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In 313 general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history 314 of sensitivity to multiple allergens (see CONTRAINDICATIONS). 315 PRECAUTIONS 316 General: Chest discomfort and jaw or neck tightness have been reported following use of 317 IMITREX Tablets and have also been reported infrequently following administration of 318 IMITREX Nasal Spray. Chest, jaw, or neck tightness is relatively common after administration 319 of IMITREX Injection. Only rarely have these symptoms been associated with ischemic ECG 320 changes. However, because sumatriptan may cause coronary artery vasospasm, patients who 321 experience signs or symptoms suggestive of angina following sumatriptan should be evaluated 322 for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving 323 additional doses of sumatriptan, and should be monitored electrocardiographically if dosing is 324 resumed and similar symptoms recur. Similarly, patients who experience other symptoms or 325 signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud 326 syndrome following sumatriptan should be evaluated for atherosclerosis or predisposition to 327 vasospasm (see WARNINGS). 328 IMITREX should also be administered with caution to patients with diseases that may alter 329 the absorption, metabolism, or excretion of drugs, such as impaired hepatic or renal function. 330 There have been rare reports of seizure following administration of sumatriptan. Sumatriptan 331 should be used with caution in patients with a history of epilepsy or conditions associated with a 332 lowered seizure threshold. 333 Care should be taken to exclude other potentially serious neurologic conditions before treating 334 headache in patients not previously diagnosed with migraine headache or who experience a 335 headache that is atypical for them. There have been rare reports where patients received 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 336 sumatriptan for severe headaches that were subsequently shown to have been secondary to an 337 evolving neurologic lesion (see WARNINGS). 338 For a given attack, if a patient does not respond to the first dose of sumatriptan, the diagnosis 339 of migraine should be reconsidered before administration of a second dose. 340 Binding to Melanin-Containing Tissues: In rats treated with a single subcutaneous dose 341 (0.5 mg/kg) or oral dose (2 mg/kg) of radiolabeled sumatriptan, the elimination half-life of 342 radioactivity from the eye was 15 and 23 days, respectively, suggesting that sumatriptan and/or 343 its metabolites bind to the melanin of the eye. Because there could be an accumulation in 344 melanin-rich tissues over time, this raises the possibility that sumatriptan could cause toxicity in 345 these tissues after extended use. However, no effects on the retina related to treatment with 346 sumatriptan were noted in any of the oral or subcutaneous toxicity studies. Although no 347 systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no 348 specific recommendations for ophthalmologic monitoring are offered, prescribers should be 349 aware of the possibility of long-term ophthalmologic effects. 350 Corneal Opacities: Sumatriptan causes corneal opacities and defects in the corneal epithelium 351 in dogs; this raises the possibility that these changes may occur in humans. While patients were 352 not systematically evaluated for these changes in clinical trials, and no specific recommendations 353 for monitoring are being offered, prescribers should be aware of the possibility of these changes 354 (see ANIMAL TOXICOLOGY). 355 Information for Patients: See PATIENT INFORMATION at the end of this labeling for the 356 text of the separate leaflet provided for patients. 357 Patients should be cautioned about the risk of serotonin syndrome with the use of sumatriptan 358 or other triptans, especially during combined use with SSRIs or SNRIs. 359 Laboratory Tests: No specific laboratory tests are recommended for monitoring patients prior 360 to and/or after treatment with sumatriptan. 361 Drug Interactions: Selective Serotonin Reuptake Inhibitors/Serotonin 362 Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of 363 life-threatening serotonin syndrome have been reported during combined use of SSRIs or SNRIs 364 and triptans (see WARNINGS). 365 Ergot-Containing Drugs: Ergot-containing drugs have been reported to cause prolonged 366 vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use 367 of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) 368 and sumatriptan within 24 hours of each other should be avoided (see 369 CONTRAINDICATIONS). 370 Monoamine Oxidase-A Inhibitors: MAO-A inhibitors reduce sumatriptan clearance, 371 significantly increasing systemic exposure. Therefore, the use of IMITREX Tablets in patients 372 receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY and 373 CONTRAINDICATIONS). 374 Drug/Laboratory Test Interactions: IMITREX Tablets are not known to interfere with 375 commonly employed clinical laboratory tests. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 376 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: In 377 carcinogenicity studies, rats and mice were given sumatriptan by oral gavage (rats, 104 weeks) or 378 drinking water (mice, 78 weeks). Average exposures achieved in mice receiving the highest dose 379 (target dose of 160 mg/kg/day) were approximately 40 times the exposure attained in humans 380 after the maximum recommended single oral dose of 100 mg. The highest dose administered to 381 rats (160 mg/kg/day, reduced from 360 mg/kg/day during week 21) was approximately 15 times 382 the maximum recommended single human oral dose of 100 mg on a mg/m2 basis. There was no 383 evidence of an increase in tumors in either species related to sumatriptan administration. 384 Mutagenesis: Sumatriptan was not mutagenic in the presence or absence of metabolic 385 activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian 386 Chinese hamster V79/HGPRT assay). In 2 cytogenetics assays (the in vitro human lymphocyte 387 assay and the in vivo rat micronucleus assay) sumatriptan was not associated with clastogenic 388 activity. 389 Impairment of Fertility: In a study in which male and female rats were dosed daily with 390 oral sumatriptan prior to and throughout the mating period, there was a treatment-related 391 decrease in fertility secondary to a decrease in mating in animals treated with 50 and 392 500 mg/kg/day. The highest no-effect dose for this finding was 5 mg/kg/day, or approximately 393 one half of the maximum recommended single human oral dose of 100 mg on a mg/m2 basis. It 394 is not clear whether the problem is associated with treatment of the males or females or both 395 combined. In a similar study by the subcutaneous route there was no evidence of impaired 396 fertility at 60 mg/kg/day, the maximum dose tested, which is equivalent to approximately 6 times 397 the maximum recommended single human oral dose of 100 mg on a mg/m2 basis. 398 Pregnancy: Pregnancy Category C. In reproductive toxicity studies in rats and rabbits, oral 399 treatment with sumatriptan was associated with embryolethality, fetal abnormalities, and pup 400 mortality. When administered by the intravenous route to rabbits, sumatriptan has been shown to 401 be embryolethal. There are no adequate and well-controlled studies in pregnant women. 402 Therefore, IMITREX should be used during pregnancy only if the potential benefit justifies the 403 potential risk to the fetus. In assessing this information, the following findings should be 404 considered. 405 Embryolethality: When given orally or intravenously to pregnant rabbits daily throughout 406 the period of organogenesis, sumatriptan caused embryolethality at doses at or close to those 407 producing maternal toxicity. In the oral studies this dose was 100 mg/kg/day, and in the 408 intravenous studies this dose was 2.0 mg/kg/day. The mechanism of the embryolethality is not 409 known. The highest no-effect dose for embryolethality by the oral route was 50 mg/kg/day, 410 which is approximately 9 times the maximum single recommended human oral dose of 100 mg 411 on a mg/m2 basis. By the intravenous route, the highest no-effect dose was 0.75 mg/kg/day, or 412 approximately one tenth of the maximum single recommended human oral dose of 100 mg on a 413 mg/m2 basis. 414 The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at 415 12.5 mg/kg/day, the maximum dose tested, did not cause embryolethality. This dose is 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 416 equivalent to the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. 417 Additionally, in a study in rats given subcutaneous sumatriptan daily prior to and throughout 418 pregnancy at 60 mg/kg/day, the maximum dose tested, there was no evidence of increased 419 embryo/fetal lethality. This dose is equivalent to approximately 6 times the maximum 420 recommended single human oral dose of 100 mg on a mg/m2 basis. 421 Teratogenicity: Oral treatment of pregnant rats with sumatriptan during the period of 422 organogenesis resulted in an increased incidence of blood vessel abnormalities (cervicothoracic 423 and umbilical) at doses of approximately 250 mg/kg/day or higher. The highest no-effect dose 424 was approximately 60 mg/kg/day, which is approximately 6 times the maximum single 425 recommended human oral dose of 100 mg on a mg/m2 basis. Oral treatment of pregnant rabbits 426 with sumatriptan during the period of organogenesis resulted in an increased incidence of 427 cervicothoracic vascular and skeletal abnormalities. The highest no-effect dose for these effects 428 was 15 mg/kg/day, or approximately 3 times the maximum single recommended human oral 429 dose of 100 mg on a mg/m2 basis. 430 A study in which rats were dosed daily with oral sumatriptan prior to and throughout gestation 431 demonstrated embryo/fetal toxicity (decreased body weight, decreased ossification, increased 432 incidence of rib variations) and an increased incidence of a syndrome of malformations (short 433 tail/short body and vertebral disorganization) at 500 mg/kg/day. The highest no-effect dose was 434 50 mg/kg/day, or approximately 5 times the maximum single recommended human oral dose of 435 100 mg on a mg/m2 basis. In a study in rats dosed daily with subcutaneous sumatriptan prior to 436 and throughout pregnancy, at a dose of 60 mg/kg/day, the maximum dose tested, there was no 437 evidence of teratogenicity. This dose is equivalent to approximately 6 times the maximum 438 recommended single human oral dose of 100 mg on a mg/m2 basis. 439 Pup Deaths: Oral treatment of pregnant rats with sumatriptan during the period of 440 organogenesis resulted in a decrease in pup survival between birth and postnatal day 4 at doses 441 of approximately 250 mg/kg/day or higher. The highest no-effect dose for this effect was 442 approximately 60 mg/kg/day, or 6 times the maximum single recommended human oral dose of 443 100 mg on a mg/m2 basis. 444 Oral treatment of pregnant rats with sumatriptan from gestational day 17 through postnatal 445 day 21 demonstrated a decrease in pup survival measured at postnatal days 2, 4, and 20 at the 446 dose of 1,000 mg/kg/day. The highest no-effect dose for this finding was 100 mg/kg/day, 447 approximately 10 times the maximum single recommended human oral dose of 100 mg on a 448 mg/m2 basis. In a similar study in rats by the subcutaneous route there was no increase in pup 449 death at 81 mg/kg/day, the highest dose tested, which is equivalent to 8 times the maximum 450 single recommended human oral dose of 100 mg on a mg/m2 basis. 451 Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to 452 IMITREX, GlaxoSmithKline maintains a Sumatriptan Pregnancy Registry. Physicians are 453 encouraged to register patients by calling (800) 336-2176. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 454 Nursing Mothers: Sumatriptan is excreted in human breast milk following subcutaneous 455 administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 456 12 hours after treatment with IMITREX Tablets. 457 Pediatric Use: Safety and effectiveness of IMITREX Tablets in pediatric patients under 18 458 years of age have not been established; therefore, IMITREX Tablets are not recommended for 459 use in patients under 18 years of age. 460 Two controlled clinical trials evaluating sumatriptan nasal spray (5 to 20 mg) in pediatric 461 patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single 462 attack. The studies did not establish the efficacy of sumatriptan nasal spray compared to placebo 463 in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were 464 similar in nature to those reported in clinical trials in adults. 465 Five controlled clinical trials (2 single attack studies, 3 multiple attack studies) evaluating oral 466 sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 467 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared 468 to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical 469 trials were similar in nature to those reported in clinical trials in adults. The frequency of all 470 adverse events in these patients appeared to be both dose- and age-dependent, with younger 471 patients reporting events more commonly than older adolescents. 472 Postmarketing experience documents that serious adverse events have occurred in the 473 pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports 474 include events similar in nature to those reported rarely in adults, including stroke, visual loss, 475 and death. A myocardial infarction has been reported in a 14-year-old male following the use of 476 oral sumatriptan; clinical signs occurred within 1 day of drug administration. Since clinical data 477 to determine the frequency of serious adverse events in pediatric patients who might receive 478 injectable, oral, or intranasal sumatriptan are not presently available, the use of sumatriptan in 479 patients aged younger than 18 years is not recommended. 480 Geriatric Use: The use of sumatriptan in elderly patients is not recommended because elderly 481 patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and 482 blood pressure increases may be more pronounced in the elderly (see WARNINGS). 483 ADVERSE REACTIONS 484 Serious cardiac events, including some that have been fatal, have occurred following the 485 use of IMITREX Injection or Tablets. These events are extremely rare and most have been 486 reported in patients with risk factors predictive of CAD. Events reported have included 487 coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, 488 ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, 489 WARNINGS, and PRECAUTIONS). 490 Significant hypertensive episodes, including hypertensive crises, have been reported on rare 491 occasions in patients with or without a history of hypertension (see WARNINGS). 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 492 Incidence in Controlled Clinical Trials: Table 2 lists adverse events that occurred in 493 placebo-controlled clinical trials in patients who took at least 1 dose of study drug. Only events 494 that occurred at a frequency of 2% or more in any group treated with IMITREX Tablets and 495 were more frequent in that group than in the placebo group are included in Table 2. The events 496 cited reflect experience gained under closely monitored conditions of clinical trials in a highly 497 selected patient population. In actual clinical practice or in other clinical trials, these frequency 498 estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients 499 treated may differ. 500 501 Table 2. Treatment-Emergent Adverse Events Reported by at Least 2% of Patients in 502 Controlled Migraine Trials* Adverse Event Type Percent of Patients Reporting Placebo (N = 309) IMITREX 25 mg (N = 417) IMITREX 50 mg (N = 771) IMITREX 100 mg (N = 437) Atypical sensations Paresthesia (all types) Sensation warm/cold 4% 2% 2% 5% 3% 3% 6% 5% 2% 6% 3% 3% Pain and other pressure sensations Chest - pain/tightness/pressure and/or heaviness Neck/throat/jaw - pain/ tightness/pressure Pain - location specified Other - pressure/tightness/ heaviness 4% 1% <1% 1% 2% 6% 1% <1% 2% 1% 6% 2% 2% 1% 1% 8% 2% 3% 1% 3% Neurological Vertigo <1% <1% <1% 2% Other Malaise/fatigue <1% 2% 2% 3% 503 * Events that occurred at a frequency of 2% or more in the group treated with IMITREX 504 Tablets and that occurred more frequently in that group than the placebo group. 505 506 Other events that occurred in more than 1% of patients receiving IMITREX Tablets and at 507 least as often on placebo included nausea and/or vomiting, migraine, headache, hyposalivation, 508 dizziness, and drowsiness/sleepiness. 509 IMITREX Tablets are generally well tolerated. Across all doses, most adverse reactions were 510 mild and transient and did not lead to long-lasting effects. The incidence of adverse events in 511 controlled clinical trials was not affected by gender or age of the patients. There were insufficient 512 data to assess the impact of race on the incidence of adverse events. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 513 Other Events Observed in Association With the Administration of IMITREX 514 Tablets: In the paragraphs that follow, the frequencies of less commonly reported adverse 515 clinical events are presented. Because the reports include events observed in open and 516 uncontrolled studies, the role of IMITREX Tablets in their causation cannot be reliably 517 determined. Furthermore, variability associated with adverse event reporting, the terminology 518 used to describe adverse events, etc., limit the value of quantitative frequency estimates 519 provided. Event frequencies are calculated as the number of patients who used IMITREX Tablets 520 (25, 50, or 100 mg) and reported an event divided by the total number of patients (N = 6,348) 521 exposed to IMITREX Tablets. All reported events are included except those already listed in the 522 previous table, those too general to be informative, and those not reasonably associated with the 523 use of the drug. Events are further classified within body system categories and enumerated in 524 order of decreasing frequency using the following definitions: frequent adverse events are 525 defined as those occurring in at least 1/100 patients, infrequent adverse events are those 526 occurring in 1/100 to 1/1,000 patients, and rare adverse events are those occurring in fewer than 527 1/1,000 patients. 528 Atypical Sensations: Frequent were burning sensation and numbness. Infrequent was tight 529 feeling in head. Rare were dysesthesia. 530 Cardiovascular: Frequent were palpitations, syncope, decreased blood pressure, and 531 increased blood pressure. Infrequent were arrhythmia, changes in ECG, hypertension, 532 hypotension, pallor, pulsating sensations, and tachycardia. Rare were angina, atherosclerosis, 533 bradycardia, cerebral ischemia, cerebrovascular lesion, heart block, peripheral cyanosis, 534 thrombosis, transient myocardial ischemia, and vasodilation. 535 Ear, Nose, and Throat: Frequent were sinusitis, tinnitus; allergic rhinitis; upper respiratory 536 inflammation; ear, nose, and throat hemorrhage; external otitis; hearing loss; nasal inflammation; 537 and sensitivity to noise. Infrequent were hearing disturbances and otalgia. Rare was feeling of 538 fullness in the ear(s). 539 Endocrine and Metabolic: Infrequent was thirst. Rare were elevated thyrotropin 540 stimulating hormone (TSH) levels; galactorrhea; hyperglycemia; hypoglycemia; hypothyroidism; 541 polydipsia; weight gain; weight loss; endocrine cysts, lumps, and masses; and fluid disturbances. 542 Eye: Rare were disorders of sclera, mydriasis, blindness and low vision, visual disturbances, 543 eye edema and swelling, eye irritation and itching, accommodation disorders, external ocular 544 muscle disorders, eye hemorrhage, eye pain, and keratitis and conjunctivitis. 545 Gastrointestinal: Frequent were diarrhea and gastric symptoms. Infrequent were 546 constipation, dysphagia, and gastroesophageal reflux. Rare were gastrointestinal bleeding, 547 hematemesis, melena, peptic ulcer, gastrointestinal pain, dyspeptic symptoms, dental pain, 548 feelings of gastrointestinal pressure, gastroesophageal reflux, gastritis, gastroenteritis, 549 hypersalivation, abdominal distention, oral itching and irritation, salivary gland swelling, and 550 swallowing disorders. 551 Hematological Disorders: Rare was anemia. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 552 Musculoskeletal: Frequent was myalgia. Infrequent was muscle cramps. Rare were tetany; 553 muscle atrophy, weakness, and tiredness; arthralgia and articular rheumatitis; acquired 554 musculoskeletal deformity; muscle stiffness, tightness, and rigidity; and musculoskeletal 555 inflammation. 556 Neurological: Frequent were phonophobia and photophobia. Infrequent were confusion, 557 depression, difficulty concentrating, disturbance of smell, dysarthria, euphoria, facial pain, heat 558 sensitivity, incoordination, lacrimation, monoplegia, sleep disturbance, shivering, syncope, and 559 tremor. Rare were aggressiveness, apathy, bradylogia, cluster headache, convulsions, decreased 560 appetite, drug abuse, dystonic reaction, facial paralysis, hallucinations, hunger, hyperesthesia, 561 hysteria, increased alertness, memory disturbance, neuralgia, paralysis, personality change, 562 phobia, radiculopathy, rigidity, suicide, twitching, agitation, anxiety, depressive disorders, 563 detachment, motor dysfunction, neurotic disorders, psychomotor disorders, taste disturbances, 564 and raised intracranial pressure. 565 Respiratory: Frequent was dyspnea. Infrequent was asthma. Rare were hiccoughs, breathing 566 disorders, cough, and bronchitis. 567 Skin: Frequent was sweating. Infrequent were erythema, pruritus, rash, and skin tenderness. 568 Rare were dry/scaly skin, tightness of skin, wrinkling of skin, eczema, seborrheic dermatitis, and 569 skin nodules. 570 Breasts: Infrequent was tenderness. Rare were nipple discharge; breast swelling; cysts, 571 lumps, and masses of breasts; and primary malignant breast neoplasm. 572 Urogenital: Infrequent were dysmenorrhea, increased urination, and intermenstrual 573 bleeding. Rare were abortion and hematuria, urinary frequency, bladder inflammation, 574 micturition disorders, urethritis, urinary infections, menstruation symptoms, abnormal menstrual 575 cycle, inflammation of fallopian tubes, and menstrual cycle symptoms. 576 Miscellaneous: Frequent was hypersensitivity. Infrequent were fever, fluid retention, and 577 overdose. Rare were edema, hematoma, lymphadenopathy, speech disturbance, voice 578 disturbances, contusions. 579 Other Events Observed in the Clinical Development of IMITREX: The following 580 adverse events occurred in clinical trials with IMITREX Injection and IMITREX Nasal Spray. 581 Because the reports include events observed in open and uncontrolled studies, the role of 582 IMITREX in their causation cannot be reliably determined. All reported events are included 583 except those already listed, those too general to be informative, and those not reasonably 584 associated with the use of the drug. 585 Atypical Sensations: Feeling strange, prickling sensation, tingling, and hot sensation. 586 Cardiovascular: Abdominal aortic aneurysm, abnormal pulse, flushing, phlebitis, Raynaud 587 syndrome, and various transient ECG changes (nonspecific ST or T wave changes, prolongation 588 of PR or QTc intervals, sinus arrhythmia, nonsustained ventricular premature beats, isolated 589 junctional ectopic beats, atrial ectopic beats, delayed activation of the right ventricle). 590 Chest Symptoms: Chest discomfort. 591 Endocrine and Metabolic: Dehydration. 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 592 Ear, Nose, and Throat: Disorder/discomfort nasal cavity and sinuses, ear infection, 593 Meniere disease, and throat discomfort. 594 Eye: Vision alterations. 595 Gastrointestinal: Abdominal discomfort, colitis, disturbance of liver function tests, 596 flatulence/eructation, gallstones, intestinal obstruction, pancreatitis, and retching. 597 Injection Site Reaction 598 Miscellaneous: Difficulty in walking, hypersensitivity to various agents, jaw discomfort, 599 miscellaneous laboratory abnormalities, “serotonin agonist effect,” swelling of the extremities, 600 and swelling of the face. 601 Mouth and Teeth: Disorder of mouth and tongue (e.g., burning of tongue, numbness of 602 tongue, dry mouth). 603 Musculoskeletal: Arthritis, backache, intervertebral disc disorder, neck pain/stiffness, need 604 to flex calf muscles, and various joint disturbances (pain, stiffness, swelling, ache). 605 Neurological: Bad/unusual taste, chills, diplegia, disturbance of emotions, sedation, globus 606 hystericus, intoxication, myoclonia, neoplasm of pituitary, relaxation, sensation of lightness, 607 simultaneous hot and cold sensations, stinging sensations, stress, tickling sensations, transient 608 hemiplegia, and yawning. 609 Respiratory: Influenza and diseases of the lower respiratory tract and lower respiratory tract 610 infection. 611 Skin: Skin eruption, herpes, and peeling of the skin. 612 Urogenital: Disorder of breasts, endometriosis, and renal calculus. 613 Postmarketing Experience (Reports for Subcutaneous or Oral Sumatriptan): The 614 following section enumerates potentially important adverse events that have occurred in clinical 615 practice and that have been reported spontaneously to various surveillance systems. The events 616 enumerated represent reports arising from both domestic and nondomestic use of oral or 617 subcutaneous dosage forms of sumatriptan. The events enumerated include all except those 618 already listed in the ADVERSE REACTIONS section above or those too general to be 619 informative. Because the reports cite events reported spontaneously from worldwide 620 postmarketing experience, frequency of events and the role of sumatriptan in their causation 621 cannot be reliably determined. It is assumed, however, that systemic reactions following 622 sumatriptan use are likely to be similar regardless of route of administration. 623 Blood: Hemolytic anemia, pancytopenia, thrombocytopenia. 624 Cardiovascular: Atrial fibrillation, cardiomyopathy, colonic ischemia (see WARNINGS), 625 Prinzmetal variant angina, pulmonary embolism, shock, thrombophlebitis. 626 Ear, Nose, and Throat: Deafness. 627 Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis, loss of 628 vision. 629 Gastrointestinal: Ischemic colitis with rectal bleeding (see WARNINGS), xerostomia. 630 Hepatic: Elevated liver function tests. 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 631 Neurological: Central nervous system vasculitis, cerebrovascular accident, dysphasia, 632 serotonin syndrome, subarachnoid hemorrhage. 633 Non-Site Specific: Angioneurotic edema, cyanosis, death (see WARNINGS), temporal 634 arteritis. 635 Psychiatry: Panic disorder. 636 Respiratory: Bronchospasm in patients with and without a history of asthma. 637 Skin: Exacerbation of sunburn, hypersensitivity reactions (allergic vasculitis, erythema, 638 pruritus, rash, shortness of breath, urticaria; in addition, severe anaphylaxis/anaphylactoid 639 reactions have been reported [see WARNINGS]), photosensitivity. 640 Urogenital: Acute renal failure. 641 DRUG ABUSE AND DEPENDENCE 642 One clinical study with IMITREX® (sumatriptan succinate) Injection enrolling 12 patients 643 with a history of substance abuse failed to induce subjective behavior and/or physiologic 644 response ordinarily associated with drugs that have an established potential for abuse. 645 OVERDOSAGE 646 Patients (N = 670) have received single oral doses of 140 to 300 mg without significant 647 adverse effects. Volunteers (N = 174) have received single oral doses of 140 to 400 mg without 648 serious adverse events. 649 Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, 650 inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, 651 salivation, and lacrimation. The elimination half-life of sumatriptan is approximately 2.5 hours 652 (see CLINICAL PHARMACOLOGY), and therefore monitoring of patients after overdose with 653 IMITREX Tablets should continue for at least 12 hours or while symptoms or signs persist. 654 It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations 655 of sumatriptan. 656 DOSAGE AND ADMINISTRATION 657 In controlled clinical trials, single doses of 25, 50, or 100 mg of IMITREX Tablets were 658 effective for the acute treatment of migraine in adults. There is evidence that doses of 50 and 659 100 mg may provide a greater effect than 25 mg (see CLINICAL TRIALS). There is also 660 evidence that doses of 100 mg do not provide a greater effect than 50 mg. Individuals may vary 661 in response to doses of IMITREX Tablets. The choice of dose should therefore be made on an 662 individual basis, weighing the possible benefit of a higher dose with the potential for a greater 663 risk of adverse events. 664 If the headache returns or the patient has a partial response to the initial dose, the dose may be 665 repeated after 2 hours, not to exceed a total daily dose of 200 mg. If a headache returns following 666 an initial treatment with IMITREX Injection, additional single IMITREX Tablets (up to 667 100 mg/day) may be given with an interval of at least 2 hours between tablet doses. The safety of 668 treating an average of more than 4 headaches in a 30-day period has not been established. 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 669 Because of the potential of MAO-A inhibitors to cause unpredictable elevations in the 670 bioavailability of oral sumatriptan, their combined use is contraindicated (see 671 CONTRAINDICATIONS). 672 Hepatic disease/functional impairment may also cause unpredictable elevations in the 673 bioavailability of orally administered sumatriptan. Consequently, if treatment is deemed 674 advisable in the presence of liver disease, the maximum single dose should in general not exceed 675 50 mg (see CLINICAL PHARMACOLOGY for the basis of this recommendation). 676 HOW SUPPLIED 677 IMITREX Tablets, 25, 50, and 100 mg of sumatriptan (base) as the succinate. 678 IMITREX Tablets, 25 mg are white, triangular-shaped, film-coated tablets debossed with “I” 679 on one side and “25” on the other in blister packs of 9 tablets (NDC 0173-0735-00). 680 IMITREX Tablets, 50 mg are white, triangular-shaped, film-coated tablets debossed with 681 “IMITREX 50” on one side and a chevron shape (^) on the other in blister packs of 9 tablets 682 (NDC 0173-0736-01). 683 IMITREX Tablets, 100 mg, are pink, triangular-shaped, film-coated tablets debossed with 684 “IMITREX 100” on one side and a chevron shape (^) on the other in blister packs of 9 tablets 685 (NDC 0173-0737-01). 686 Store between 36° and 86°F (2° and 30°C). 687 ANIMAL TOXICOLOGY 688 Corneal Opacities: Dogs receiving oral sumatriptan developed corneal opacities and defects 689 in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 2 mg/kg/day, 690 and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 691 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses 692 were not established; however, the relative exposure at the lowest dose tested was approximately 693 5 times the human exposure after a 100-mg oral dose. There is evidence of alterations in corneal 694 appearance on the first day of intranasal dosing to dogs. Changes were noted at the lowest dose 695 tested, which was approximately one half the maximum single human oral dose of 100 mg on a 696 mg/m2 basis. 697 PATIENT INFORMATION 698 The following wording is contained in a separate leaflet provided for patients. 699 700 Information for the Patient 701 IMITREX®* (sumatriptan succinate) Tablets 702 703 Please read this leaflet carefully before you take IMITREX Tablets. This provides a summary of 704 the information available on your medicine. Please do not throw away this leaflet until you have 705 finished your medicine. You may need to read this leaflet again. This leaflet does not contain all 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 706 the information on IMITREX Tablets. For further information or advice, ask your doctor or 707 pharmacist. 708 Information About Your Medicine: 709 The name of your medicine is IMITREX (sumatriptan succinate) Tablets. It can be obtained 710 only by prescription from your doctor. The decision to use IMITREX Tablets is one that you and 711 your doctor should make jointly, taking into account your individual preferences and medical 712 circumstances. If you have risk factors for heart disease (such as high blood pressure, high 713 cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are 714 postmenopausal or a male over 40 years of age), you should tell your doctor, who should 715 evaluate you for heart disease in order to determine if IMITREX is appropriate for you. Although 716 the vast majority of those who have taken IMITREX have not experienced any significant side 717 effects, some individuals have experienced serious heart problems and, rarely, considering the 718 extensiveness of IMITREX use worldwide, deaths have been reported. In all but a few instances, 719 however, serious problems occurred in people with known heart disease and it was not clear 720 whether IMITREX was a contributory factor in these deaths. 721 1. The Purpose of Your Medicine: 722 IMITREX Tablets are intended to relieve your migraine, but not to prevent or reduce the 723 number of attacks you experience. Use IMITREX Tablets only to treat an actual migraine attack. 724 2. Important Questions to Consider Before Taking IMITREX Tablets: 725 If the answer to any of the following questions is YES or if you do not know the answer, then 726 please discuss it with your doctor before you use IMITREX Tablets. 727 • Are you pregnant? Do you think you might be pregnant? Are you trying to become pregnant? 728 Are you using inadequate contraception? Are you breastfeeding? 729 • Do you have any chest pain, heart disease, shortness of breath, or irregular heartbeats? Have 730 you had a heart attack? 731 • Do you have risk factors for heart disease (such as high blood pressure, high cholesterol, 732 obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal 733 or a male over 40 years of age)? 734 • Have you had a stroke, transient ischemic attacks (TIAs), or Raynaud syndrome? 735 • Do you have high blood pressure? 736 • Have you ever had to stop taking this or any other medicine because of an allergy or other 737 problems? 738 • Are you taking any other migraine medicines, including other 5-HT1 agonists or any other 739 medicines containing ergotamine, dihydroergotamine, or methysergide? 740 • Are you taking any medicine for depression or other disorders such as monoamine oxidase 741 inhibitors, selective serotonin reuptake inhibitors (SSRIs), or serotonin norepinephrine 742 reuptake inhibitors (SNRIs)? Common SSRIs are citalopram HBr (CELEXA®), escitalopram 743 oxalate (LEXAPRO®), paroxetine (PAXIL®), fluoxetine (PROZAC®/SARAFEM®), 744 olanzapine/fluoxetine (SYMBYAX®), sertraline (ZOLOFT®), and fluvoxamine. Common 745 SNRIs are duloxetine (CYMBALTA®) and venlafaxine (EFFEXOR®).* 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 746 • Have you had, or do you have, any disease of the liver or kidney? 747 • Have you had, or do you have, epilepsy or seizures? 748 • Is this headache different from your usual migraine attacks? 749 Remember, if you answered YES to any of the above questions, then discuss it with your 750 doctor. 751 3. The Use of IMITREX Tablets During Pregnancy: 752 Do not use IMITREX Tablets if you are pregnant, think you might be pregnant, are trying to 753 become pregnant, or are not using adequate contraception, unless you have discussed this with 754 your doctor. 755 4. How to Use IMITREX Tablets: 756 For adults, the usual dose is a single tablet swallowed whole with water or other fluids. Do not 757 split tablets. 758 A second tablet may be taken if your symptoms of migraine come back or if you have a 759 partial response to the initial dose, but not sooner than 2 hours following the first tablet. For a 760 given attack, if you have no response to the first tablet, do not take a second tablet without first 761 consulting with your doctor. Do not take more than a total of 200 mg of IMITREX Tablets in 762 any 24-hour period. The safety of treating an average of more than 4 headaches in a 30-day 763 period has not been established. 764 5. Side Effects to Watch for: 765 • Some patients experience pain or tightness in the chest or throat when using IMITREX 766 Tablets. If this happens to you, then discuss it with your doctor before using any more 767 IMITREX Tablets. If the chest pain is severe or does not go away, call your doctor 768 immediately. 769 • If you have sudden and/or severe abdominal pain following IMITREX Tablets, call your 770 doctor immediately. 771 • Some people may have a reaction called serotonin syndrome when they use certain types of 772 antidepressants, SSRIs or SNRIs, while taking IMITREX Tablets. Symptoms may include 773 confusion, hallucinations, fast heartbeat, feeling faint, fever, sweating, muscle spasm, 774 difficulty walking, and/or diarrhea. Call your doctor immediately if you have any of these 775 symptoms after taking IMITREX Tablets. 776 • Shortness of breath; wheeziness; heart throbbing; swelling of eyelids, face, or lips; or a skin 777 rash, skin lumps, or hives happens rarely. If it happens to you, then tell your doctor 778 immediately. Do not take any more IMITREX Tablets unless your doctor tells you to do so. 779 • Some people may have feelings of tingling, heat, flushing (redness of face lasting a short 780 time), heaviness or pressure after treatment with IMITREX Tablets. A few people may feel 781 drowsy, dizzy, tired, or sick. Tell your doctor of these symptoms at your next visit. 782 • If you feel unwell in any other way or have any symptoms that you do not understand, you 783 should contact your doctor immediately. 784 6. What to Do if an Overdose is Taken: 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 785 If you have taken more medicine than you have been told, contact either your doctor, hospital 786 emergency department, or nearest poison control center immediately. 787 7. Storing Your Medicine: 788 Keep your medicine in a safe place where children cannot reach it. It may be harmful to 789 children. Do not remove tablets from the packaging until you are ready to use them. Do not store 790 the tablets in any other container. 791 Store your medicine away from heat and light. Do not store at temperatures above 86°F 792 (30°C), or below 36°F (2°C). 793 If your medicine has expired (the expiration date is printed on the treatment pack), throw it 794 away as instructed. If your doctor decides to stop your treatment, do not keep any leftover 795 medicine unless your doctor tells you to. Throw away your medicine as instructed. 796 797 *IMITREX and PAXIL are registered trademarks of GlaxoSmithKline. The other brands listed 798 are trademarks of their respective owners and are not trademarks of GlaxoSmithKline. The 799 makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its 800 products. 801 802 company logo 804 GlaxoSmithKline 805 Research Triangle Park, NC 27709 806 807 ©2007, GlaxoSmithKline. All rights reserved. 808 809 April 2007 RL-2363 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.968210	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020132s013s020s021s022lbl.pdf', 'application_number': 20132, 'submission_type': 'SUPPL ', 'submission_number': 20}
12,246	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Fusilev safely and effectively. See full prescribing information for Fusilev. Fusilev (levoleucovorin) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION for INTRAVENOUS use Initial U.S. Approval: 1952 (d,l-leucovorin), 2008 (levoleucovorin) --------------------INDICATIONS AND USAGE-------------------- Fusilev is a folate analog. (1) Fusilev rescue is indicated after high-dose methotrexate therapy in osteosarcoma. (1) Fusilev is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. (1) Limitations of Use Fusilev is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. (1.1) --------------------DOSAGE AND ADMINISTRATION-------------------- Fusilev Rescue After High-Dose Methotrexate Therapy Do not administer intrathecally. (2.1) Fusilev is dosed at one-half the usual dose of the racemic form. (2.1) Fusilev rescue recommendations are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours. Fusilev rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Determine serum creatinine and methotrexate levels at least once daily. Continue Fusilev administration, hydration, and urinary alkalinization (pH of 7.0 or greater) until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The Fusilev dose may need to be adjusted. (2.3) --------------------DOSAGE FORMS AND STRENGTHS------------------- Each 50 mg single-use vial of Fusilev contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin ) and 50 mg mannitol. (16) It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride for Injection, USP. (2.5, 11) --------------------CONTRAINDICATIONS-------------------- Fusilev is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. (4) --------------------WARNINGS AND PRECAUTIONS------------------- Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. (5.1) Fusilev enhances the toxicity of fluorouracil. (5.2,7) Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study. (5.3) --------------------ADVERSE REACTIONS------------------- Allergic reactions were reported in patients receiving Fusilev. (6.2) Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving Fusilev as rescue after high dose methotrexate therapy. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Spectrum Pharmaceuticals, Inc. at 1-877-387-4538 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch --------------------DRUG INTERACTIONS-------------------- Fusilev may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients. (7) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Administration Guidelines 2.2 Co-administration of Fusilev with other agents 2.3 Fusilev Rescue After High-Dose Methotrexate Therapy 2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage 2.5 Reconstitution and Infusion Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Rate of Administration 5.2 Potential for Enhanced Toxicity with 5-Fluorouracil 5.3 Potential for interaction with trimethoprim-sulfamethoxazole 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility 13.2 Animal Toxicology And/Or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING *Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE • Fusilev™ is a folate analog. • Fusilev rescue is indicated after high-dose methotrexate therapy in osteosarcoma. • Fusilev is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. 1.1 Limitations of Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Fusilev is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. 2 DOSAGE AND ADMINISTRATION 2.1 Administration Guidelines Fusilev is dosed at one-half the usual dose of the racemic form. Fusilev is indicated for intravenous administration only. Do not administer intrathecally. 2.2 Co-administration of Fusilev with other agents Due to the risk of precipitation, do not co-administer Fusilev with other agents in the same admixture. 2.3 Fusilev Rescue After High-Dose Methotrexate Therapy The recommendations for Fusilev rescue are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). Fusilev rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Serum creatinine and methotrexate levels should be determined at least once daily. Fusilev administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The Fusilev dose should be adjusted or rescue extended based on the following guidelines. Table 1 Guidelines for Fusilev Dosage and Administration Clinical Situation Laboratory Findings Fusilev Dosage and Duration Normal Serum methotrexate level approximately 10 7.5 mg IV q 6 hours for 60 Methotrexate Elimination micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than Continue 7.5 mg IV q 6 hours, until methotrexate level is less Elimination 0.05 micromolar at 96 hours after administration. than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or 75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 Evidence of Acute Renal Injury greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., hours until methotrexate level is less than 0.05 micromolar. an increase from 0.5 mg/dL to a level of 1 mg/dL or more). Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate Fusilev therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, Fusilev rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed. Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of Fusilev or prolonged administration may be indicated. Although Fusilev may ameliorate the hematologic toxicity associated with high dose methotrexate, Fusilev has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney. 2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage Fusilev rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and Fusilev rescue increases, Fusilev’s effectiveness in counteracting toxicity may decrease. Fusilev 7.5 mg (approximately 5 mg/m2 ) should be administered IV every 6 hours until the serum methotrexate level is less than 10-8 M. Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of Fusilev should be increased to 50 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater. 2.5 Reconstitution and Infusion Instructions • Prior to intravenous injection, the 50 mg vial of Fusilev for Injection is reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives (e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended. • The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. • Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or further dilution using 0.9% Sodium Chloride Injection, USP may be held at room temperature for not more than a total of 12 hours. Dilutions in 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours. • Visually inspect the reconstituted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed. • No more than 16 mL of reconstituted solutions (160 mg of levoleucovorin ) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution. 3 DOSAGE FORMS AND STRENGTHS Fusilev is supplied in sterile, single-use vials containing 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin ) and 50 mg mannitol. 4 CONTRAINDICATIONS Fusilev is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. 5 WARNINGS AND PRECAUTIONS 5.1 Rate of Administration Because of the Ca++ content of the levoleucovorin solution, no more than 16 mL (160 mg of levoleucovorin ) should be injected intravenously per minute. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.2 Potential for Enhanced Toxicity with 5-Fluorouracil Fusilev enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. 5.3 Potential for interaction with trimethoprim-sulfamethoxazole The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Since clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following table presents the frequency of adverse reactions which occurred during the administration of 58 courses of high dose methotrexate 12 grams/m2 followed by Fusilev rescue for osteosarcoma in 16 patients age 6-21. Most patients received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Table 2 Adverse Reactions Body System/Adverse Reactions Number (%) of Patients with Adverse Reactions (N =16) All Grade 3+ Number (%) of Courses with Adverse Reactions (N = 58) All Grade 3+ Gastrointestinal Stomatitis Vomiting Nausea Diarrhea Dyspepsia Typhlitis Respiratory Dyspnea Skin and Appendages Dermatitis Other Confusion Neuropathy Renal function abnormal Taste perversion Total number of patients Total number of courses 6 (37.5) 1 (6.3) 6 (37.5) 0 3 (18.8) 0 1 (6.3) 0 1 (6.3) 0 1 (6.3) 1 (6.3) 1 (6.3) 0 1 (6.3) 0 1 (6.3) 0 1 (6.3) 0 1 (6.3) 0 1 (6.3) 0 9 (56.3) 25 (43.1) 10 (17.2) 1 (1.7) 14 (24.1) 0 3 (5.2) 0 1 (1.7) 0 1 (1.7) 0 1 (1.7) 1 (1.7) 1 (1.7) 0 1 (1.7) 0 1 (1.7) 0 1 (1.7) 0 3 (5.2) 0 1 (1.7) 0 2 (12.5) 2 (3.4) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high dose methotrexate with Fusilev rescue because patients were receiving other myelosuppressive chemotherapy. 6.2 Postmarketing Experience Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reaction.” 7 DRUG INTERACTIONS Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects. However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs. Preliminary human studies have shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. Fusilev increases the toxicity of 5-fluorouracil [see Warnings and Precautions (5.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. It is not known whether Fusilev can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. Animal reproduction studies have not been conducted with Fusilev. Fusilev should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fusilev is administered to a nursing mother. 8.4 Pediatric Use [See Clinical Studies (14)] 8.5 Geriatric Use Clinical studies of Fusilev in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. 10 OVERDOSAGE No data are available for overdosage with levoleucovorin. 11 DESCRIPTION Levoleucovorin is the levo isomeric form of racemic d,l-leucovorin, present as the calcium salt. Levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin]. Fusilev for injection contains levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by methotrexate. This compound has the chemical designation calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl}-L-glutamate pentahydrate. The molecular weight is 601.6 and the structural formula is: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chemical Structure Its molecular formula is: C20H21CaN7O7 . 5 H2O. Fusilev for injection is supplied as a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol per 50 mg vial. Sodium hydroxide and/or hydrocholoric acid are used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride Injection, USP [See Dosage and Administration (2.5)] 12 CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one carbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. 12.2 Pharmacodynamics Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5 methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5 methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate. 12.3 Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8 tetrahydrofolate was 5.1 and 6.8 hours, respectively. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility. 13.2 Animal Toxicology And/Or Pharmacology The acute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m2) and 378 mg/kg ( 2268 mg/m2), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m2, which represents a 3-log safety margin. 14 CLINICAL STUDIES The safety and efficacy of Fusilev rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m2 IV over 4 hours was administered to 13 patients, who received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m2 IV over 6 hours, followed by Fusilev 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of Fusilev doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of Fusilev rescue following high-dose methotrexate was based on the adverse reaction profile. [See Adverse Reactions (6)] 16 HOW SUPPLIED/STORAGE AND HANDLING Each 50 mg single-use vial of Fusilev for Injection contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol. 50 mg vial of freeze-dried powder – NDC 68152-101-00. Store at 25° C (77 °F) in carton until contents are used. Excursions permitted from 15-30° C (59-86 °F). [See USP Controlled Room Temperature]. Protect from light. Spectrum Logo Manufactured for Spectrum Pharmaceuticals, Inc. Irvine, CA 92618 Manufactured by Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230 Spectrum Pharmaceuticals, Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:48.977041	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020140s001lbl.pdf', 'application_number': 20140, 'submission_type': 'SUPPL ', 'submission_number': 1}
12,247	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Fusilev safely and effectively. See full prescribing information for Fusilev. Fusilev® (levoleucovorin) FOR INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION for INTRAVENOUS use Fusilev® (levoleucovorin) INJECTION, SOLUTION for INTRAVENOUS use Initial U.S. Approval: 1952 (d,l-leucovorin), 2008 (levoleucovorin) --------------------RECENT MAJOR CHANGES------------------- Indications and Usage (1) 04/2011 Dosage and Administration, Fusilev Administration in Combination with 5-Fluorouracil (2.5) 04/2011 Dosage and Administration, Reconstitution and Infusion Instructions (2.6) 04/2011 --------------------INDICATIONS AND USAGE-------------------- Fusilev is a folate analog indicated for: • Rescue after high-dose methotrexate therapy in osteosarcoma. • Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. • Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.(1) Limitations of Use Fusilev is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. (1.1) --------------------DOSAGE AND ADMINISTRATION------------------- Do not administer intrathecally. (2.1) Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin. (2.1) Fusilev Rescue After High-Dose Methotrexate Therapy Fusilev rescue recommendations are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours. Fusilev rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Determine serum creatinine and methotrexate levels at least once daily. Continue Fusilev administration, hydration, and urinary alkalinization (pH of 7.0 or greater) until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The Fusilev dose may need to be adjusted. (2.3) Fusilev Administration in Combination with 5-Fluorouracil (5-FU) The following regimens have been used historically for the treatment of colorectal cancer: 1. Fusilev is administered at 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m2 by intravenous injection. (2.5) 2. Fusilev is administered at 10 mg/m by 2 intravenous injection followed by 5-FU at 425 mg/m2 by intravenous injection. (2.5) 5-FU and Fusilev should be administered separately to avoid the formation of a precipitate. Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course. In subsequent treatment courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-FU should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity. For patients who experienced no toxicity in the prior treatment course, 5-FU dosage may be increased by 10%. Fusilev dosages are not adjusted for toxicity. (2.5) -------------------DOSAGE FORMS AND STRENGTHS-------------------- Fusilev for Injection: Each 50 mg single-use vial of Fusilev contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin ) and 50 mg mannitol. (3, 11, 16) It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride Injection, USP. (2.6, 11) Fusilev Injection: 17.5 mL of a sterile solution containing levoleucovorin calcium pentahydrate equivalent to 175 mg levoleucovorin and 0.83% sodium chloride. (3, 11, 16) Fusilev Injection: 25 mL of a sterile solution containing levoleucovorin calcium pentahydrate equivalent to 250 mg levoleucovorin and 0.83% sodium chloride. (3, 11, 16) --------------------CONTRAINDICATIONS-------------------- Fusilev is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. (4) --------------------WARNINGS AND PRECAUTIONS------------------- Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. (5.1) Fusilev enhances the toxicity of fluorouracil. (5.2,7) Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study. (5.3) --------------------ADVERSE REACTIONS------------------- Allergic reactions were reported in patients receiving Fusilev. (6.3) Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving Fusilev as rescue after high-dose methotrexate therapy. (6.1) The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving Fusilev in combination with 5-FU were diarrhea, nausea and stomatitis. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Spectrum Pharmaceuticals, Inc. at 1-877-387-4538 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch --------------------DRUG INTERACTIONS-------------------- Fusilev may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients. (7) Revised: [04/2011] FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Administration Guidelines 2.2 Co-administration of Fusilev with other agents 2.3 Fusilev Rescue After High-Dose Methotrexate Therapy 2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage 2.5 Fusilev Administration in Combination with 5-Fluorouracil (5-FU) 2.6 Reconstitution and Infusion Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Rate of Administration 5.2 Potential for Enhanced Toxicity with 5-Fluorouracil 5.3 Potential for interaction with trimethoprim-sulfamethoxazole 6 ADVERSE REACTIONS 6.1 Clinical Studies in High-Dose Methotrexate Therapy 6.2 Clinical Studies in Combination with 5-FU in Colorectal Cancer 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility 13.2 Animal Toxicology And/Or Pharmacology 14 CLINICAL STUDIES 14.1 High-Dose Methotrexate Therapy 14.2 Combination with 5-FU in Colorectal Cancer 16 HOW SUPPLIED/STORAGE AND HANDLING *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 INDICATIONS AND USAGE • Fusilev® is a folate analog. • Fusilev rescue is indicated after high-dose methotrexate therapy in osteosarcoma. • Fusilev is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. • Fusilev is indicated for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. 1.1 Limitations of Use • Fusilev is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. 2 DOSAGE AND ADMINISTRATION 2.1 Administration Guidelines Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin. Fusilev is indicated for intravenous administration only. Do not administer intrathecally. 2.2 Co-administration of Fusilev with other agents Due to the risk of precipitation, do not co-administer Fusilev with other agents in the same admixture. 2.3 Fusilev Rescue After High-Dose Methotrexate Therapy The recommendations for Fusilev rescue are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). Fusilev rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Serum creatinine and methotrexate levels should be determined at least once daily. Fusilev administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The Fusilev dose should be adjusted or rescue extended based on the following guidelines. Table 1 Guidelines for Fusilev Dosage and Administration Clinical Situation Laboratory Findings Fusilev Dosage and Duration Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours 7.5 mg IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 7.5 mg IV q 6 hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar. FULL PRESCRIBING INFORMATION Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate Fusilev therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, Fusilev rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed. Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of Fusilev or prolonged administration may be indicated. Although Fusilev may ameliorate the hematologic toxicity associated with high-dose methotrexate, Fusilev has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney. 2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage Fusilev rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and Fusilev rescue increases, Fusilev’s effectiveness in counteracting toxicity may decrease. Fusilev 7.5 mg (approximately 5 mg/m2 ) should be administered IV every 6 hours until the serum methotrexate level is less than 10-8 M. Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of Fusilev should be increased to 50 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater. 2.5 Fusilev Administration in Combination with 5-Fluorouracil (5-FU) The following regimens have been used historically for the treatment of colorectal cancer: 1. Fusilev is administered at 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m2 by intravenous injection. 2. Fusilev is administered at 10 mg/m2 by intravenous injection followed by 5-FU at 425 mg/m2 by intravenous injection. 5-FU and Fusilev should be administered separately to avoid the formation of a precipitate. Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course. In subsequent treatment courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-FU should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity. For patients who experienced no toxicity in the prior treatment course, 5-FU dosage may be increased by 10%. Fusilev dosages are not adjusted for toxicity. 2.6 Reconstitution and Infusion Instructions Fusilev for Injection • Prior to intravenous injection, the 50 mg vial of Fusilev for Injection is reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chloride solutions with preservatives (e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended. • The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. • Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or further dilution using 0.9% Sodium Chloride Injection, USP may be held at room temperature for not more than a total of 12 hours. Dilutions in 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours. • Visually inspect the reconstituted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed. • No more than 16 mL of reconstituted solutions (160 mg of levoleucovorin) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution. Fusilev Injection • Levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. • Levoleucovorin solutions may be further diluted to concentrations of 0.5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The diluted solution using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours. • Visually inspect the diluted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed. • No more than 16 mL of Fusilev Injection (160 mg of levoleucovorin) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution. 3 DOSAGE FORMS AND STRENGTHS Fusilev for Injection is supplied in sterile, single-use vials containing 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol. Fusilev Injection, 175 mg is supplied in a single-use vial containing 17.5 mL sterile solution. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. Fusilev Injection, 250 mg is supplied in a single-use vial containing 25 mL sterile solution. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. 4 CONTRAINDICATIONS Fusilev is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. 5 WARNINGS AND PRECAUTIONS 5.1 Rate of Administration Because of the Ca++ content of the levoleucovorin solution, no more than 16 mL (160 mg of levoleucovorin) should be injected intravenously per minute. 5.2 Potential for Enhanced Toxicity with 5-Fluorouracil Fusilev enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the toxicities observed in patients treated with the combination of Fusilev and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination. In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-FU alone or 5-FU in combination with 200 mg/m2 of d,l-leucovorin and 20% when Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treated with 5-FU in combination with 20 mg/m2 of d,l-leucovorin. In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose d,l-leucovorin/5-FU combination than in patients treated with the high dose combination – 11% versus 3%. Therapy with Fusilev and 5-FU must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. In an additional study utilizing higher weekly doses of 5-FU and d,l-leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity. Seizures and/or syncope have been reported rarely in cancer patients receiving d,l-leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors. However, a causal relationship has not been established. 5.3 Potential for interaction with trimethoprim-sulfamethoxazole The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study. 6 ADVERSE REACTIONS 6.1 Clinical Studies in High-Dose Methotrexate Therapy Since clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following table presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m2 followed by Fusilev rescue for osteosarcoma in 16 patients age 6-21. Most patients received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Table 2 Adverse Reactions with High-Dose Methotrexate Therapy Body System/Adverse Reactions Number (%) of Patients with Adverse Reactions (N =16) All Grade 3+ Number (%) of Courses with Adverse Reactions (N = 58) All Grade 3+ Gastrointestinal Stomatitis Vomiting Nausea Diarrhea Dyspepsia Typhlitis Respiratory Dyspnea Skin and Appendages Dermatitis Other Confusion Neuropathy Renal function abnormal Taste perversion Total number of patients 6 (37.5) 1 (6.3) 6 (37.5) 0 3 (18.8) 0 1 (6.3) 0 1 (6.3) 0 1 (6.3) 1 (6.3) 1 (6.3) 0 1 (6.3) 0 1 (6.3) 0 1 (6.3) 0 1 (6.3) 0 1 (6.3) 0 9 (56.3) 10 (17.2) 1 (1.7) 14 (24.1) 0 3 (5.2) 0 1 (1.7) 0 1 (1.7) 0 1 (1.7) 1 (1.7) 1 (1.7) 0 1 (1.7) 0 1 (1.7) 0 1 (1.7) 0 3 (5.2) 0 1 (1.7) 0 2 (12.5) Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Total number of courses 25 (43.1) 2 (3.4) The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high-dose methotrexate with Fusilev rescue because patients were receiving other myelosuppressive chemotherapy. 6.2 Clinical Studies in Combination with 5-FU in Colorectal Cancer A randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with advanced colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l-leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. The following table presents the most frequent adverse reactions which occurred in patients in the 2 treatment arms. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm Adverse Reaction Levoleucovorin/5FU n=318 d,l-Leucovorin/5FU n=307 Adverse Event N (%) Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Gastrointestinal Disorders Stomatitis 229 (72%) 37 (12%) 221 (72%) 44 (14%) Diarrhea 222 (70%) 61 (19%) 201 (65%) 51 (17%) Nausea 197 (62%) 25 (8%) 186 (61%) 26 (8%) Vomiting 128 (40%) 17 (5%) 114 (37%) 18 (6%) Abdominal Pain1 45 (14%) 10 (3%) 57 (19%) 10 (3%) General Disorders Asthenia/Fatigue/Malaise 91 (29%) 15 (5%) 99 (32%) 34 (11%) Metabolism and Nutrition Anorexia/Decreased Appetite 76 (24%) 13 (4%) 77 (25%) 5 (2%) Skin Disorders Dermatitis 91 (29%) 3 (1%) 86 (28%) 4 (1%) Alopecia 83 (26%) 1 (0.3%) 87 (28%) 3 (1%) 1Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness 6.3 Postmarketing Experience Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reactions.” In an analysis where calcium levoleucovorin was reported as the primary suspect drug and fluorouracil (FU) was reported as a concomitant medication, possible allergic reactions were reported among 47 cases (67 events). 7 DRUG INTERACTIONS Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects. Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs. Preliminary human studies have shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. Fusilev increases the toxicity of 5-fluorouracil [see Warnings and Precautions (5.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Fusilev. It is not known whether Fusilev can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Fusilev should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Fusilev, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use [See Clinical Studies (14)] 8.5 Geriatric Use Clinical studies of Fusilev in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. In the NCCTG clinical trial of Fusilev in combination with 5-FU in advanced colorectal cancer, adverse reactions were consistent with 5-FU related toxicity and were similar for patients age 65 and older and for patients younger than age 65. 10 OVERDOSAGE No data are available for overdosage with levoleucovorin. 11 DESCRIPTION Levoleucovorin is the levo isomeric form of racemic d,l-leucovorin, present as the calcium salt. Levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin]. Fusilev for Injection and Fusilev Injection contain levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by methotrexate. This compound has the chemical designation calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6 pteridinyl)methyl] amino]benzoyl}-L-glutamate pentahydrate. The molecular weight is 601.6 and the structural formula is: structural formula Its molecular formula is: C20H21CaN7O7 . 5 H2O. Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fusilev for Injection is supplied as a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol per 50 mg vial. Sodium hydroxide and/or hydrocholoric acid are used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride Injection, USP [See Dosage and Administration (2.6)] Fusilev Injection is supplied as a sterile solution of either 175 mg levoleucovorin in 17.5 mL or 250 mg levoleucovorin in 25 mL. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. Sodium hydroxide is used for pH adjustment to pH 8.0 (6.5 to 8.5). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action 12.1.1 Levoleucovorin effects during high-dose methotrexate therapy Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one carbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. 12.1.2 Levoleucovorin effects in combination with 5-fluorouracil Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme. 12.2 Pharmacodynamics Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate. 12.3 Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8 tetrahydrofolate was 5.1 and 6.8 hours, respectively. A pharmacokinetic study was conducted in 40 healthy subjects who received a single intravenous dose of either Fusilev (200 mg/m2 ) or racemic d,l-leucovorin (400 mg/m2), each administered as a 2-hour infusion in a crossover design. Results indicate that the 90% confidence interval for the geometric mean ratios for both AUC0-inf and Cmax were within the standard limit of 80-125% for both l-leucovorin and l-5-methyl-THF. Therefore, the exposure to l-leucovorin and 5-methyl-THF (AUC0-inf and Cmax) was comparable whether it was administered as Fusilev or as d,l-leucovorin. The geometric mean AUC0-inf values for levoleucovorin were 30719 ng.h/mL and 31296 ng.h/mL for Fusilev and d,l-leucovorin, respectively. The geometric mean Cmax values for levoleucovorin were 10895 ng/mL and 11301 ng/ mL for Fusilev and d,l-leucovorin, respectively. The geometric mean AUC0-inf values for 5-methyl-THF were 52105 ng.h/mL and 50137 ng.h/mL for Fusilev and d,l-leucovorin, respectively. The geometric mean Cmax values for 5-methyl-THF were 4930 ng/mL and 4658 ng/mL for Fusilev and d,l-leucovorin, respectively. Use of Levoleucovorin in combination with 5-fluorouracil A published cross study comparison showed that the mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether 5-FU (370 mg/m2/day IV bolus) was given in combination with levoleucovorin (250 mg/m2 and 1000 mg/m2 as a continuous IV infusion for 5.5 days, N=9) or in combination with d,l-leucovorin (500 mg/m2 as a continuous IV infusion for 5.5 days, N=6). Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility. 13.2 Animal Toxicology And/Or Pharmacology The acute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m2) and 378 mg/kg (2268 mg/m2), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m2 for high-dose methotrexate therapy which represents a 3-log safety margin. 14 CLINICAL STUDIES 14.1 High-Dose Methotrexate Therapy The safety and efficacy of Fusilev rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m2 IV over 4 hours was administered to 13 patients, who received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m2 IV over 6 hours, followed by Fusilev 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of Fusilev doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of Fusilev rescue following high-dose methotrexate was based on the adverse reaction profile. [See Adverse Reactions (6)] 14.2 Combination with 5-FU in Colorectal Cancer In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer, three treatment regimens were compared: d,l-leucovorin (LV) 200 mg/m2 and 5-fluorouracil (5-FU) 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus 5-FU 500 mg/m2. All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days. Response rates were 26% (p=0.04 versus 5-FU alone), 43% (p=0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose LV regimen gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose LV regimen gave a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant. In a second Mayo/NCCTG randomized clinical study the 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV. Response rates with LV 200 mg/m2 and 5-FU 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus sequential MTX and 5-FU and LV were respectively 31% (p≤0.01), 42% (p≤0.01), and 14%. Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months. No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms. A randomized controlled trial conducted by the NCCTG in patients with advanced metastatic colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l-leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin. 16 HOW SUPPLIED/STORAGE AND HANDLING Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Each 50 mg single-use vial of Fusilev for Injection contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol. 50 mg vial of freeze-dried powder – NDC 68152-101-00. Store at 25° C (77 °F) in carton until contents are used. Excursions permitted from 15-30° C (59-86 °F). [See USP Controlled Room Temperature]. Protect from light. Fusilev Injection, 175 mg contains 17.5 mL sterile solution in a single-use vial. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. 175 mg/17.5 mL solution – NDC 68152-102-01 Fusilev Injection, 250 mg contains 25 mL sterile solution in a single-use vial. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. 250 mg/25 mL solution – NDC 68152-102-02 Store in refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in carton until contents are used. Manufactured for Spectrum Pharmaceuticals, Inc. Irvine, CA 92618 1125-000503 Fusilev® is a registered trademark of Spectrum Pharmaceuticals, Inc. Spectrum Pharmaceuticals, Inc. Reference ID: 2939597 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:49.442616	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf', 'application_number': 20140, 'submission_type': 'SUPPL ', 'submission_number': 2}
12,248	structural formula company logo Cataflam® (diclofenac potassium immediate-release tablets) Tablets of 50 mg Rx only Prescribing Information CARDIOVASCULAR RISK • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS.) • Cataflam® (diclofenac potassium immediate-release tablets) is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). GASTROINTESTINAL RISK • NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.) DESCRIPTION Cataflam® (diclofenac potassium immediate-release tablets) is a benzeneacetic acid derivative. Cataflam is available as immediate-release tablets of 50 mg (light brown) for oral administration. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monopotassium salt. The molecular weight is 334.25. Its molecular formula is C14H10Cl2NKO2, and it has the following structural formula Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The inactive ingredients in Cataflam include: calcium phosphate, colloidal silicon dioxide, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, maize starch, sucrose, talc, titanium dioxide. CLINICAL PHARMACOLOGY Pharmacodynamics Cataflam® (diclofenac potassium immediate-release tablets) is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Cataflam, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Absorption Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). In some fasting volunteers, measurable plasma levels are observed within 10 minutes of dosing with Cataflam. Peak plasma levels are achieved approximately 1 hour in fasting normal volunteers, with a range of .33 to 2 hours. Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption and a reduction in peak plasma levels of approximately 30%. Table 1. Pharmacokinetic Parameters for Diclofenac Normal Healthy Adults PK Parameter (20-52 yrs.) Coefficient of Mean Variation (%) Absolute Bioavailability (%) 55 40 [N = 7] Tmax (hr) 1.0 76 [N = 65] Oral Clearance (CL/F; mL/min) 622 21 [N = 61] Renal Clearance <1 — (% unchanged drug in urine) [N = 7] Apparent Volume of 1.3 33 Distribution (V/F; L/kg) [N = 61] Terminal Half-life (hr) 1.9 29 [N = 48] Distribution The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 µg/mL) achieved with recommended doses. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy-diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy-diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy- and 3’-hydroxy-diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4' hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours. Drug Interactions When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the Cmax and AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS, Drug Interactions). Special Populations Pediatric: The pharmacokinetics of Cataflam has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Insufficiency: Hepatic metabolism accounts for almost 100% of Cataflam elimination, so patients with hepatic disease may require reduced doses of Cataflam compared to patients with normal hepatic function. Renal Insufficiency: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Cataflam® (diclofenac potassium immediate- release tablets) and other treatment options before deciding to use Cataflam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Cataflam is indicated: ● For treatment of primary dysmenorrhea ● For relief of mild to moderate pain ● For relief of the signs and symptoms of osteoarthritis ● For relief of the signs and symptoms of rheumatoid arthritis CONTRAINDICATIONS Cataflam® (diclofenac potassium immediate-release tablets) is contraindicated in patients with known hypersensitivity to diclofenac. Cataflam should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactic Reactions, and PRECAUTIONS, Preexisting Asthma). Cataflam is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, GI Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypertension NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Cataflam, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Cataflam should be used with caution in patients with fluid retention or heart failure. Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including Cataflam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Caution should be used when initiating treatment with Cataflam in patients with considerable dehydration. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Cataflam in patients with advanced renal disease. Therefore, treatment with Cataflam is not recommended in these patients with advanced renal disease. If Cataflam therapy must be initiated, close monitoring of the patient’s renal function is advisable. Hepatic Effects Elevations of one or more liver tests may occur during therapy with Cataflam. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury. In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Cataflam should be discontinued immediately. To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu like" symptoms), and the appropriate action patients should take if these signs and symptoms appear. To minimize the potential risk for an adverse liver related event in patients treated with Cataflam, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing Cataflam with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics). Anaphylactic Reactions As with other NSAIDs, anaphylactic reactions may occur both in patients with the aspirin triad and in patients without known sensitivity to NSAIDs or known prior exposure to Cataflam. Cataflam should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. (See CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma.) Anaphylaxis-type reactions have been reported with NSAID products, including with diclofenac products, such as Cataflam. Emergency help should be sought in cases where an anaphylactic reaction occurs. Skin Reactions NSAIDs, including Cataflam, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, Cataflam should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Cataflam® (diclofenac potassium immediate-release tablets) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Cataflam in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including Cataflam. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Cataflam, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients receiving Cataflam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Cataflam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Cataflam, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Cataflam, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation). 3. Cataflam, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy (see WARNINGS, Hepatic Effects). 6. Patients should be informed of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactic Reactions). 7. In late pregnancy, as with other NSAIDs, Cataflam should be avoided because it will cause premature closure of the ductus arteriosus. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long-term treatment with NSAIDs, including Cataflam, CBC and a chemistry profile (including transaminase levels) should be checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Cataflam should be discontinued. Drug Interactions Aspirin: When Cataflam is administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects. Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Cyclosporine: Cataflam, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with Cataflam may increase cyclosporine’s nephrotoxicity. Caution should be used when Cataflam is administered concomitantly with cyclosporine. ACE Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Furosemide: Clinical studies, as well as postmarketing observations, have shown that Cataflam can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. CYP2C9 Inhibitors or Inducers: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. Use caution when dosing diclofenac with CYP2C9 inhibitors or inducers, a dosage adjustment may be warranted (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions). Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Teratogenic Effects: Pregnancy Category C Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Nonteratogenic Effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Cataflam on labor and delivery in pregnant women are unknown. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cataflam, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ADVERSE REACTIONS In 718 patients treated for shorter periods, i.e., 2 weeks or less, with Cataflam® (diclofenac potassium immediate-release tablets), adverse reactions were reported one-half to one-tenth as frequently as by patients treated for longer periods. In a 6-month, double-blind trial comparing Cataflam (N=196) versus Voltaren® (diclofenac sodium delayed-release tablets) (N=197) versus ibuprofen (N=197), adverse reactions were similar in nature and frequency. In patients taking Cataflam or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting. Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus. Additional adverse experiences reported occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: asthma, dyspnea Skin and Appendages: alopecia, photosensitivity, sweating increased Special Senses: blurred vision Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions, which occur rarely are: Body as a Whole: anaphylactic reactions, appetite changes, death Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System: colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional: hyperglycemia Nervous System: convulsions, coma, hallucinations, meningitis Respiratory System: respiratory depression, pneumonia Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special Senses: conjunctivitis, hearing impairment OVERDOSAGE Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Cataflam® (diclofenac potassium immediate- release tablets) and other treatment options before deciding to use Cataflam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with Cataflam, the dose and frequency should be adjusted to suit an individual patient’s needs. For treatment of pain or primary dysmenorrhea the recommended dosage is 50 mg t.i.d. With experience, physicians may find that in some patients an initial dose of 100 mg of Cataflam, followed by 50-mg doses, will provide better relief. For the relief of osteoarthritis the recommended dosage is 100-150 mg/day in divided doses, 50 mg b.i.d. or t.i.d. For the relief of rheumatoid arthritis the recommended dosage is 150-200 mg/day in divided doses, 50 mg t.i.d. or q.i.d. Different formulations of diclofenac [Voltaren® (diclofenac sodium enteric-coated tablets); Voltaren®-XR (diclofenac sodium extended-release tablets); Cataflam® (diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the milligram strength is the same. HOW SUPPLIED Cataflam® (diclofenac potassium immediate-release tablets) 50 mg – light brown, round, biconvex, sugar-coated tablets (imprinted Cataflam on one side and 50 on the other side in black ink) Bottles of 100……..……………….……………………………..NDC 0078-0436-05 Do not store above 30°C (86°F). Dispense in tight container (USP). MEDICATION GUIDE FOR NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)." NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: • can happen without warning symptoms Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called "corticosteroids" and "anticoagulants" • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: Other side effects include: Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pains • flu-like symptoms • vomit blood Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over the counter). Talk to your healthcare provider before using over the counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda * Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. The brands listed are the trademarks or register marks of their respective owners and are not trademarks or register marks of Novartis. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Patheon Inc., Whitby Operations Ontario, Canada L1N 5Z5 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 REV: February 2011 T2009-32/T2009-33 © Novartis Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:49.492101	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020142s021s022lbl.pdf', 'application_number': 20142, 'submission_type': 'SUPPL ', 'submission_number': 21}
12,249	structural formula company logo Cataflam® (diclofenac potassium immediate-release tablets) Tablets of 50 mg Rx only Prescribing Information CARDIOVASCULAR RISK • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS.) • Cataflam® (diclofenac potassium immediate-release tablets) is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). GASTROINTESTINAL RISK • NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.) DESCRIPTION Cataflam® (diclofenac potassium immediate-release tablets) is a benzeneacetic acid derivative. Cataflam is available as immediate-release tablets of 50 mg (light brown) for oral administration. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monopotassium salt. The molecular weight is 334.25. Its molecular formula is C14H10Cl2NKO2, and it has the following structural formula Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The inactive ingredients in Cataflam include: calcium phosphate, colloidal silicon dioxide, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, maize starch, sucrose, talc, titanium dioxide. CLINICAL PHARMACOLOGY Pharmacodynamics Cataflam® (diclofenac potassium immediate-release tablets) is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Cataflam, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Absorption Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). In some fasting volunteers, measurable plasma levels are observed within 10 minutes of dosing with Cataflam. Peak plasma levels are achieved approximately 1 hour in fasting normal volunteers, with a range of .33 to 2 hours. Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption and a reduction in peak plasma levels of approximately 30%. Table 1. Pharmacokinetic Parameters for Diclofenac Normal Healthy Adults PK Parameter (20-52 yrs.) Coefficient of Mean Variation (%) Absolute Bioavailability (%) 55 40 [N = 7] Tmax (hr) 1.0 76 [N = 65] Oral Clearance (CL/F; mL/min) 622 21 [N = 61] Renal Clearance <1 — (% unchanged drug in urine) [N = 7] Apparent Volume of 1.3 33 Distribution (V/F; L/kg) [N = 61] Terminal Half-life (hr) 1.9 29 [N = 48] Distribution The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 µg/mL) achieved with recommended doses. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy-diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy-diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy- and 3’-hydroxy-diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4' hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours. Drug Interactions When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the Cmax and AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS, Drug Interactions). Special Populations Pediatric: The pharmacokinetics of Cataflam has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Insufficiency: Hepatic metabolism accounts for almost 100% of Cataflam elimination, so patients with hepatic disease may require reduced doses of Cataflam compared to patients with normal hepatic function. Renal Insufficiency: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Cataflam® (diclofenac potassium immediate- release tablets) and other treatment options before deciding to use Cataflam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Cataflam is indicated: ● For treatment of primary dysmenorrhea ● For relief of mild to moderate pain ● For relief of the signs and symptoms of osteoarthritis ● For relief of the signs and symptoms of rheumatoid arthritis CONTRAINDICATIONS Cataflam® (diclofenac potassium immediate-release tablets) is contraindicated in patients with known hypersensitivity to diclofenac. Cataflam should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactic Reactions, and PRECAUTIONS, Preexisting Asthma). Cataflam is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, GI Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hypertension NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Cataflam, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Cataflam should be used with caution in patients with fluid retention or heart failure. Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including Cataflam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Caution should be used when initiating treatment with Cataflam in patients with considerable dehydration. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Cataflam in patients with advanced renal disease. Therefore, treatment with Cataflam is not recommended in these patients with advanced renal disease. If Cataflam therapy must be initiated, close monitoring of the patient’s renal function is advisable. Hepatic Effects Elevations of one or more liver tests may occur during therapy with Cataflam. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury. In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Cataflam should be discontinued immediately. To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu like" symptoms), and the appropriate action patients should take if these signs and symptoms appear. To minimize the potential risk for an adverse liver related event in patients treated with Cataflam, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing Cataflam with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics). Anaphylactic Reactions As with other NSAIDs, anaphylactic reactions may occur both in patients with the aspirin triad and in patients without known sensitivity to NSAIDs or known prior exposure to Cataflam. Cataflam should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. (See CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma.) Anaphylaxis-type reactions have been reported with NSAID products, including with diclofenac products, such as Cataflam. Emergency help should be sought in cases where an anaphylactic reaction occurs. Skin Reactions NSAIDs, including Cataflam, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, Cataflam should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Cataflam® (diclofenac potassium immediate-release tablets) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Cataflam in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including Cataflam. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Cataflam, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients receiving Cataflam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Cataflam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Cataflam, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Cataflam, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation). 3. Cataflam, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy (see WARNINGS, Hepatic Effects). 6. Patients should be informed of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactic Reactions). 7. In late pregnancy, as with other NSAIDs, Cataflam should be avoided because it will cause premature closure of the ductus arteriosus. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long-term treatment with NSAIDs, including Cataflam, CBC and a chemistry profile (including transaminase levels) should be checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Cataflam should be discontinued. Drug Interactions Aspirin: When Cataflam is administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects. Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Cyclosporine: Cataflam, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with Cataflam may increase cyclosporine’s nephrotoxicity. Caution should be used when Cataflam is administered concomitantly with cyclosporine. ACE Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Furosemide: Clinical studies, as well as postmarketing observations, have shown that Cataflam can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. CYP2C9 Inhibitors or Inducers: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. Use caution when dosing diclofenac with CYP2C9 inhibitors or inducers, a dosage adjustment may be warranted (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions). Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Teratogenic Effects: Pregnancy Category C Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Nonteratogenic Effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Cataflam on labor and delivery in pregnant women are unknown. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cataflam, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ADVERSE REACTIONS In 718 patients treated for shorter periods, i.e., 2 weeks or less, with Cataflam® (diclofenac potassium immediate-release tablets), adverse reactions were reported one-half to one-tenth as frequently as by patients treated for longer periods. In a 6-month, double-blind trial comparing Cataflam (N=196) versus Voltaren® (diclofenac sodium delayed-release tablets) (N=197) versus ibuprofen (N=197), adverse reactions were similar in nature and frequency. In patients taking Cataflam or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting. Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus. Additional adverse experiences reported occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: asthma, dyspnea Skin and Appendages: alopecia, photosensitivity, sweating increased Special Senses: blurred vision Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions, which occur rarely are: Body as a Whole: anaphylactic reactions, appetite changes, death Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System: colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional: hyperglycemia Nervous System: convulsions, coma, hallucinations, meningitis Respiratory System: respiratory depression, pneumonia Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special Senses: conjunctivitis, hearing impairment OVERDOSAGE Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Cataflam® (diclofenac potassium immediate- release tablets) and other treatment options before deciding to use Cataflam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with Cataflam, the dose and frequency should be adjusted to suit an individual patient’s needs. For treatment of pain or primary dysmenorrhea the recommended dosage is 50 mg t.i.d. With experience, physicians may find that in some patients an initial dose of 100 mg of Cataflam, followed by 50-mg doses, will provide better relief. For the relief of osteoarthritis the recommended dosage is 100-150 mg/day in divided doses, 50 mg b.i.d. or t.i.d. For the relief of rheumatoid arthritis the recommended dosage is 150-200 mg/day in divided doses, 50 mg t.i.d. or q.i.d. Different formulations of diclofenac [Voltaren® (diclofenac sodium enteric-coated tablets); Voltaren®-XR (diclofenac sodium extended-release tablets); Cataflam® (diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the milligram strength is the same. HOW SUPPLIED Cataflam® (diclofenac potassium immediate-release tablets) 50 mg – light brown, round, biconvex, sugar-coated tablets (imprinted Cataflam on one side and 50 on the other side in black ink) Bottles of 100……..……………….……………………………..NDC 0078-0436-05 Do not store above 30°C (86°F). Dispense in tight container (USP). MEDICATION GUIDE FOR NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)." NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: • can happen without warning symptoms Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called "corticosteroids" and "anticoagulants" • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: Other side effects include: Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pains • flu-like symptoms • vomit blood Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over the counter). Talk to your healthcare provider before using over the counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda * Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. The brands listed are the trademarks or register marks of their respective owners and are not trademarks or register marks of Novartis. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Patheon Inc., Whitby Operations Ontario, Canada L1N 5Z5 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 REV: February 2011 T2009-32/T2009-33 © Novartis Reference ID: 2909337 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:49.555025	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020142s021s022lbl.pdf', 'application_number': 20142, 'submission_type': 'SUPPL ', 'submission_number': 22}
12,250	N5-929 S-032 S-033 Package Insert Page 1 T2001-89 89014801 D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Rx only Prescribing Information WARNING Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of DIHYDROERGOTAMINE, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated. (See also CONTRAINDICATIONS and WARNINGS section) DESCRIPTION D.H.E. 45® is ergotamine hydrogenated in the 9, 10 position as the mesylate salt. D.H.E. 45® is known chemically as ergotaman-3´,6´,18-trione,9,10-dihydro-12´-hydroxy-2´-methyl-5´-(phenylmethyl)-,(5´α)-, monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is C33H37N5O5⋅CH4O3S. The chemical structure is Dihydroergotamine mesylate C33H37N5O5⋅CH4O3S Mol. wt. 679.80 D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is a clear, colorless solution supplied in sterile ampuls for I.V., I.M., or subcutaneous administration containing per mL: dihydroergotamine mesylate, USP.......................................................................................1 mg ethanol, 94% w/w....................................................................................................6.2% by vol. glycerin..................................................................................................................... 15% by wt. water for injection, qs to .................................................................................................... 1 mL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 2 CLINICAL PHARMACOLOGY Mechanism of Action Dihydroergotamine binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline α2A, α2B and α, receptors, and dopamine D2L and D3 receptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine. One theory suggests that activation of 5-HT1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro- inflammatory neuropeptide release. In addition, dihydroergotamine possesses oxytocic properties. (See CONTRAINDICATIONS.) Pharmacokinetics Absorption Absolute bioavailability for the subcutaneous and intramuscular route have not been determined, however, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses. Dihydroergotamine mesylate is poorly bioavailable following oral administration. Distribution Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters. Metabolism Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8´-β-hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, i.e., dihydrolysergic acid, dihydrolysergic amide, and a metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20%-30% of plasma AUC. Quantitative pharmacokinetic characterization of the four metabolites has not been performed. Excretion The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. Only 6%-7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with a terminal half-life of about 9 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 3 Subpopulations No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is contraindicated in patients with severely impaired hepatic or renal function. (See CONTRAINDICATIONS.) Interactions Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g. ritonavir), presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (See CONTRAINDICATIONS). No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. INDICATIONS AND USAGE D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is indicated for the acute treatment of migraine headaches with or without aura and the acute treatment of cluster headache episodes. CONTRAINDICATIONS There have been a few reports of serious adverse events associated with the coadministration of dihydroergotamine and potent CYP 3A4 inhibitors, such as protease inhibitors and macrolide antibiotics, resulting in vasospasm that led to cerebral ischemia and/or ischemia of the extremities. The use of potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole) with dihydroergotamine is, therefore contraindicated (See WARNINGS: CYP 3A4 Inhibitors). D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should not be given to patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have clinical symptoms or findings consistent with coronary artery vasospasm including Prinzmetal’s variant angina. (See WARNINGS.) Because D.H.E. 45® (dihydroergotamine mesylate) Injection, USP may increase blood pressure, it should not be given to patients with uncontrolled hypertension. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should not be administered to patients with hemiplegic or basilar migraine. In addition to those conditions mentioned above, D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery and severely impaired hepatic or renal function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 4 D.H.E. 45® (dihydroergotamine mesylate) Injection, USP may cause fetal harm when administered to a pregnant woman. Dihydroergotamine possesses oxytocic properties and, therefore, should not be administered during pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. There are no adequate studies of dihydroergotamine in human pregnancy, but developmental toxicity has been demonstrated in experimental animals. In embryo-fetal development studies of dihydroergotamine mesylate nasal spray, intranasal administration to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weights and/or skeletal ossification at doses of 0.16 mg/day (associated with maternal plasma dihydroergotamine exposures [AUC] approximately 0.4-1.2 times the exposures in humans receiving the MRDD of 4 mg) or greater. A no effect level for embryo-fetal toxicity was not established in rats. Delayed skeletal ossification was also noted in rabbit fetuses following intranasal administration of 3.6 mg/day (maternal exposures approximately 7 times human exposures at the MRDD) during organogenesis. A no effect level was seen at 1.2 mg/day (maternal exposures approximately 2.5 times human exposures at the MRDD). When dihydroergotamine mesylate nasal spray was administered intranasally to female rats during pregnancy and lactation, decreased body weights and impaired reproductive function (decreased mating indices) were observed in the offspring at doses of 0.16 mg/day or greater. A no effect level was not established. Effects on development occurred at doses below those that produced evidence of significant maternal toxicity in these studies. Dihydroergotamine-induced intrauterine growth retardation has been attributed to reduced uteroplacental blood flow resulting from prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids. Dihydroergotamine mesylate should not be used by nursing mothers. (See PRECAUTIONS.) Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure. WARNINGS D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should only be used where a clear diagnosis of migraine headache has been established. CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of dihydroergotamine and potent CYP 3A4 inhibitors, such as protease inhibitors and macrolide antibiotics, resulting in vasospasm that led to cerebral ischemia and/or and ischemia of the extremities. The use of potent CYP 3A4 inhibitors with dihydroergotamine should therefore be avoided (see CONTRAINDICATIONS). Examples of some of the more potent CYP 3A4 inhibitors include: anti-fungals ketoconazole and itraconazole, the protease inhibitors ritonavir, nelfinavir, and indinavir, and macrolide antibiotics erythromycin, clarithromycin, and troleandomycin. Other less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP3A4 of other agents being considered for concomitant use with dihydroergotamine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 5 Fibrotic Complications There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of injectable dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs has been associated with cardiac valvular fibrosis. Rare cases have also been reported in association with the use of injectable dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with cardiac valvular fibrosis. Administration of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION). Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should not be used by patients with documented ischemic or vasospastic coronary artery disease. (See CONTRAINDICATIONS.) It is strongly recommended that D.H.E. 45® (dihydroergotamine mesylate) Injection, USP not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, females who are surgically or physiologically postmenopausal, or males who are over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should not be administered. (See CONTRAINDICATIONS.) For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received dihydroergotamine mesylate. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, in those patients with risk factors. It is recommended that patients who are intermittent long-term users of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. The systematic approach described above is currently recommended as a method to identify patients in whom D.H.E. 45® (dihydroergotamine mesylate) Injection, USP may be used to treat migraine headaches with an acceptable margin of cardiovascular safety. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 6 Cardiac Events and Fatalities The potential for adverse cardiac events exists. Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported to have occurred following the administration of dihydroergotamine mesylate injection. Considering the extent of use of dihydroergotamine mesylate in patients with migraine, the incidence of these events is extremely low. Drug-Associated Cerebrovascular Events and Fatalities Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with D.H.E. 45® (dihydroergotamine mesylate) Injection, USP; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the D.H.E. 45® (dihydroergotamine mesylate) Injection, USP having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Other Vasospasm Related Events D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial, peripheral vascular, and colonic ischemia have been reported with D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP associated vasospastic phenomena may also cause muscle pains, numbness, coldness, pallor, and cyanosis of the digits. In patients with compromised circulation, persistent vasospasm may result in gangrene or death. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should be discontinued immediately if signs or symptoms of vasoconstriction develop. Increase In Blood Pressure Significant elevation in blood pressure has been reported on rare occasions in patients with and without a history of hypertension treated with dihydroergotamine mesylate injection. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is contraindicated in patients with uncontrolled hypertension. (See CONTRAINDICATIONS.) An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1 agonist in a study evaluating subjects undergoing cardiac catheterization. PRECAUTIONS General D.H.E. 45® (dihydroergotamine mesylate) Injection, USP may cause coronary artery vasospasm; patients who experience signs or symptoms suggestive of angina following its administration should, therefore, be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud’s syndrome following the use of any 5-HT agonist are candidates for further evaluation. (See WARNINGS.) Fibrotic Complications: see WARNINGS: Fibrotic Complications This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 7 Information for Patients The text of a patient information sheet is printed at the end of this insert. To assure safe and effective use of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, the information and instructions provided in the patient information sheet should be discussed with patients. Patients should be advised to report to the physician immediately any of the following: numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest, temporary speeding or slowing of the heart rate, swelling, or itching. Prior to the initial use of the product by a patient, the prescriber should take steps to ensure that the patient understands how to use the product as provided. (See Patient Information Sheet and product packaging.) Administration of D.H.E. 45® (dihydroergotamine mesylate) Injection , USP, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION). Drug Interactions Vasoconstrictors D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure. Sumatriptan Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. Sumatriptan and D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should not be taken within 24 hours of each other. (See CONTRAINDICATIONS.) Beta Blockers Although the results of a clinical study did not indicate a safety problem associated with the administration of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP to subjects already receiving propranolol, there have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine. Nicotine Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 8 CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS. SSRI’s Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT1 agonists have been co- administered with SSRI’s (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRI’s and D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. Oral Contraceptives The effect of oral contraceptives on the pharmacokinetics of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP has not been studied. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing. Mutagenesis Dihydroergotamine mesylate was clastogenic in two in vitro chromosomal aberration assays, the V79 Chinese hamster cell assay with metabolic activation and the cultured human peripheral blood lymphocyte assay. There was no evidence of mutagenic potential when dihydroergotamine mesylate was tested in the presence or absence of metabolic activation in two gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay) and in an assay for DNA damage (the rat hepatocyte unscheduled DNA synthesis test). Dihydroergotamine was not clastogenic in the in vivo mouse and hamster micronucleus tests. Impairment of Fertility Impairment of fertility was not evaluated for D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. There was no evidence of impairment of fertility in rats given intranasal doses of Migranal® Nasal Spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately 9 to 11 times those in humans receiving the MRDD of 4 mg). Pregnancy Pregnancy Category X. See CONTRAINDICATIONS. Nursing Mothers Ergot drugs are known to inhibit prolactin. It is likely that D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is excreted in human milk, but there are no data on the concentration of dihydroergotamine in human milk. It is known that ergotamine is excreted in breast milk and may cause vomiting, diarrhea, weak pulse, and unstable blood pressure in nursing infants. Because of the potential for these serious adverse events in nursing infants exposed to D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 9 nursing should not be undertaken with the use of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. (See CONTRAINDICATIONS.) Pediatric Use Safety and effectiveness in pediatric patients have not been established. ADVERSE REACTIONS Serious cardiac events, including some that have been fatal, have occurred following use of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, but are extremely rare. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS.). Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate (see WARNINGS: Fibrotic Complications). Post-introduction Reports The following events derived from postmarketing experience have been occasionally reported in patients receiving D.H.E. 45® (dihydroergotamine mesylate) Injection, USP: vasospasm, paraesthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, and pleural and retroperitoneal fibrosis after long-term use of dihydroergotamine. Extremely rare cases of myocardial infarction and stroke have been reported. A causal relationship has not been established. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is not recommended for prolonged daily use. (See DOSAGE AND ADMINISTRATION.) DRUG ABUSE AND DEPENDENCE Currently available data have not demonstrated drug abuse or psychological dependence with dihydroergotamine. However, cases of drug abuse and psychological dependence in patients on other forms of ergot therapy have been reported. Thus, due to the chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages. OVERDOSAGE To date, there have been no reports of acute overdosage with this drug. Due to the risk of vascular spasm, exceeding the recommended dosages of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is to be avoided. Excessive doses of dihydroergotamine may result in peripheral signs and symptoms of ergotism. Treatment includes discontinuance of the drug, local application of warmth to the affected area, the administration of vasodilators, and nursing care to prevent tissue damage. In general, the symptoms of an acute D.H.E. 45® (dihydroergotamine mesylate) Injection, USP overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. The symptoms of an ergotamine overdose include the following: numbness, tingling, pain, and cyanosis of the extremities associated with diminished or absent peripheral pulses; respiratory depression; an increase and/or decrease in blood pressure, usually in that order; confusion, delirium, convulsions, and coma; and/or some degree of nausea, vomiting, and abdominal pain. In laboratory animals, significant lethality occurs when dihydroergotamine is given at I.V. doses of 44 mg/kg in mice, 130 mg/kg in rats, and 37 mg/kg in rabbits. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 10 Up-to-date information about the treatment of overdosage can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physician’s Desk Reference® (PDR).* DOSAGE AND ADMINISTRATION D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should be administered in a dose of 1 mL intravenously, intramuscularly or subcutaneously. The dose can be repeated, as needed, at 1 hour intervals to a total dose of 3 mL for intramuscular or subcutaneous delivery or 2 mL for intravenous delivery in a 24 hour period. The total weekly dosage should not exceed 6 mL. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, should not be used for chronic daily administration. HOW SUPPLIED D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Available as a clear, colorless, sterile solution in single 1 mL sterile ampuls containing 1 mg of dihydroergotamine mesylate per mL, in packages of 10 (NDC 0078-0041-01). Store below 25°C (77°F), in light-resistant containers. Do not refrigerate or freeze. To assure constant potency, protect the ampuls from light and heat. Administer only if clear and colorless. INSTRUCTION FOR PATIENTS ON SUBCUTANEOUS SELF-INJECTION Information for the Patient D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Before self-injecting D.H.E. 45® (dihydroergotamine mesylate) Injection, USP by subcutaneous administration, you will need to obtain professional instruction on how to properly administer your medication. Below are some of the steps you should follow carefully. Read this leaflet completely before using this medication. This leaflet does not contain all of the information on D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. Your pharmacist and/or health care provider can provide more detailed information. Purpose of your Medication D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is intended to treat an active migraine headache. Do not try to use it to prevent a headache if you have no symptoms. Do not use it to treat common tension headache or a headache that is not at all typical of your usual migraine headache. Administration of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, should not exceed the dosing guidelines and should not be used for chronic daily administration. There have been reports of fibrosis (stiffening) in the lung or kidney areas in patients following prolonged daily use of injectable dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs (the class of drugs to which D.H.E. 45® dihydroergotamine mesylate Injection, USP belongs) has been associated with heart valvular fibrosis. Rare cases have also been reported in association with the use of injectable dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with heart valvular fibrosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 11 Do not use D.H.E. 45® (dihydroergotamine mesylate) Injection, USP if you: • are pregnant or nursing. • have any disease affecting your heart, arteries, or circulation. • are taking certain anti-HIV medications (protease inhibitors). • are taking a macrolide antibiotic such as toleandomycin, clarithromycin or erythromycin. Important questions to consider before using D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Please answer the following questions before you use your D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. If you answer YES to any of these questions or are unsure of the answer, you should talk to your doctor before using D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. • Do you have high blood pressure? • Do you have chest pain, shortness of breath, heart disease, or have you had any surgery on your heart arteries? • Do you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal or a male over 40)? • Do you have any problems with blood circulation in your arms or legs, fingers, or toes? • Are you pregnant? Do you think you might be pregnant? Are you trying to become pregnant? Are you sexually active and not using birth control? Are you breast feeding? • Have you ever had to stop taking this or any other medication because of an allergy or bad reaction? • Are you taking any other migraine medications, erythromycin or other antibiotics, or medications for blood pressure prescribed by your doctor, or other medicines obtained from your drugstore without a doctor’s prescription? • Do you smoke? • Have you had, or do you have, any disease of the liver or kidney? • Is this headache different from your usual migraine attacks? • Are you using D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Spray or other dihydroergotamine mesylate containing drugs on a daily basis? • Are you taking a protease inhibitor for HIV therapy? • Are you taking a macrolide class of antibiotic? Serious or potentially life-threatening reductions in blood flow to the brain or extremities have been reported rarely due to interactions between D.H.E. 45 and protease inhibitors or macrolide antibiotics. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 12 REMEMBER TO TELL YOUR DOCTOR IF YOU HAVE ANSWERED YES TO ANY OF THESE QUESTIONS BEFORE YOU USE D.H.E. 45® (dihydroergotamine mesylate) Injection, USP Side Effects To Watch Out For Although the following reactions rarely occur, they can be serious and should be reported to your physician immediately: • Numbness or tingling in your fingers and toes. • Pain, tightness, or discomfort in your chest. • Muscle pain or cramps in your arms and legs. • Weakness in your legs. • Temporary speeding or slowing of your heart rate. • Swelling or itching. Dosage Your doctor will have told you what dose to use for each migraine attack. Should you get another migraine attack in the same day as the attack you treated, you must not treat it with D.H.E. 45® (dihydroergotamine mesylate) Injection, USP unless at least 6 hours have elapsed since your last injection. No more than 6 mL of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should be injected during a one-week period. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is not intended to be used on a prolonged daily basis. Learn what to do in case of an Overdose If you have used more medication than you have been instructed, contact your doctor, hospital emergency department, or nearest poison control center immediately. How to use the D.H.E. 45® (dihydroergotamine mesylate) Injection, USP 1. Use available training materials. • Read and follow the instructions in the patient instruction booklet which is provided with the D.H.E. 45® (dihydroergotamine mesylate) Injection, USP package before attempting to use the product. • If there are any questions concerning the use of your D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, ask your Doctor or pharmacist. 2. Preparing for the Injection • Carefully examine the ampul (glass vial) of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP for any cracks or breaks, and the liquid for discoloration, cloudiness, or particles. If any of these defects are present, use a new ampul, make certain it is intact, and return the defective ampul to your doctor or pharmacy. Once you open an ampul, if it is not used within an hour, it should be thrown away. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 13 3. Locating an Injection Site • Administer your subcutaneous Injection in the middle of your thigh, well above the knee. 4. Drawing the Medication into the Syringe • Wash your hands thoroughly with soap and water. • Check the dose of your medication. • Look to see if there is any liquid at the top of the ampul. If there is, gently flick the ampul with your finger to get all the liquid into the bottom portion of the ampul. • Hold the bottom of the ampul in one hand. To break, place the thumb of the other hand on the dot as shown and snap off backwards. Instructions for Use One-point-cut ampul with cut below colored dot. To break, place thumb on the dot and snap back. • Tilt the ampul down at a 45° angle. Insert the needle into the solution in the ampul. • Draw up the medication by pulling back the plunger slowly and steadily until you reach your dose. • Check the syringe for air bubbles. Hold it with the needle pointing upward. If there are air bubbles, tap your finger against the barrel of the syringe to get the bubbles to the top. Slowly and carefully push the plunger up so that the bubbles are pushed out through the needle and you see a drop of medication. • When there are no air bubbles, check the dose of the medication. If the dose is incorrect, repeat steps 6 through 8 until you draw up the right dose. 5. Preparing the Injection Site • With a new alcohol wipe, clean the selected injection site thoroughly with a firm, circular motion from inside to outside. Wait for the injection site to dry before injecting. 6. Administering the Injection • Hold the syringe/needle in your right hand. • With your left hand, firmly grasp about a 1-inch fold of skin at the injection site. • Push the needle shaft, bevel side up, all the way into the fold of skin at a 45° to 90° angle, then release the fold of skin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N5-929 S-032 S-033 Package Insert Page 14 • While holding the syringe with your left hand, use your right hand to draw back slightly on the plunger. • If you do not see any blood coming back into the syringe, inject the medication by pushing down on the plunger. If you do see blood in the syringe, that means the needle has penetrated a vein. If this happens, pull the needle/syringe out of the skin slightly and draw back on the plunger again. If no blood is seen this time, inject the medication. • Use your right hand to pull the needle out of your skin quickly at the same angle you injected it. Immediately press the alcohol wipe on the injection site and rub. Check the expiration date printed on the ampul containing medication. If the expiration date has passed, do not use it. Answers to patients’ questions about D.H.E. 45® (dihydroergotamine mesylate) Injection, USP What if I need help in using my D.H.E. 45® (dihydroergotamine mesylate) Injection, USP? If you have any questions or if you need help in opening, putting together, or using D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, speak to your doctor or pharmacist. How much medication should I use and how often? Your doctor will have told you what dose to use for each migraine attack. Should you get another migraine attack in the same day as the attack you treated, you must not treat it with D.H.E. 45® (dihydroergotamine mesylate) Injection, USP unless at least 6 hours have elapsed since your last injection. No more than 6 mL of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should be injected during a one-week period. Do not use more than this amount unless instructed to do so by your doctor. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is not intended for chronic daily use. If you have any other unanswered question about D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, consult your doctor or pharmacist. Trademark of Medical Economics Company, Inc. Manufactured by: Distributed by: Novartis Pharma AG Novartis Pharmaceuticals Corporation Basle, Switzerland East Hanover, New Jersey 07936 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 1 T2000-79 89011901 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray The solution used in Migranal® (dihydroergotamine mesylate, USP) Nasal Spray (4 mg/mL) is intended for intranasal use and must not be injected. Rx Only WARNING Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of DIHYDROERGOTAMINE, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated. (See also CONTRAINDICATIONS and WARNINGS section) DESCRIPTION Migranal® is ergotamine hydrogenated in the 9,10 position as the mesylate salt. Migranal® is known chemically as ergotaman-3’,6’,18-trione,9,10-dihydro-12’-hydroxy-2’-methyl-5’-(phenylmethyl)-,(5’α)- ,monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is C33H37N5O5·CH403S. The chemical structure is: Dihydroergotamine mesylate C33H37N5O5•CH4O3S Mol. wt. 679.80 MigranaI® (dihydroergotamine mesylate, USP) Nasal Spray is provided for intranasal administration as a clear, colorless to faintly yellow solution in an amber glass ampul containing: dihydroergotamine mesylate, USP............................................................................4.0 mg caffeine, anhydrous, USP........................................................................................10.0 mg dextrose, anhydrous, USP .......................................................................................50.0 mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 2 carbon dioxide.................................................................................................................. qs water for injection, USP.......................................................................................qs 1.0 mL CLINICAL PHARMACOLOGY Mechanism of Action Dihydroergotamine binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline α2A, α2B and α1 receptors, and dopamine D2L and D3 receptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine. One theory suggests that activation of 5-HT1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. In addition, dihydroergotamine possesses oxytocic properties. (See CONTRAINDICATIONS) Pharmacokinetics Absorption Dihydroergotamine mesylate is poorly bioavailable following oral administration. Following intranasal administration, however, the mean bioavailability of dihydroergotamine mesylate is 32% relative to the injectable administration. Absorption is variable, probably reflecting both intersubject differences of absorption and the technique used for self-administration. Distribution Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters. Metabolism Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8’-β-hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, i.e., dihydrolysergic acid, dihydrolysergic amide and a metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20%-30% of plasma AUC. The systemic clearance of dihydroergotamine mesylate following I.V. and I.M. administration is 1.5 L/min. Quantitative pharmacokinetic characterization of the four metabolites has not been performed. Excretion The major excretory route of dihydroergotamine is via the bile in the feces. After intranasal administration the urinary recovery of parent drug amounts to about 2% of the administered dose compared to 6% after I.M. administration. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 3 renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine is biphasic with a terminal half-life of about 10 hours. Subpopulations No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is contraindicated in patients with severely impaired hepatic or renal function. (See CONTRAINDICATIONS) Interactions The pharmacokinetics of dihydroergotamine did not appear to be significantly affected by the concomitant use of a local vasoconstrictor (e.g., fenoxazoline). Multiple oral doses of the β-adrenoceptor antagonist propranolol, used for migraine prophylaxis, had no significant influence on the Cmax, Tmax or AUC of dihydroergotamine doses up to 4 mg. Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g. ritonavir), presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (See CONTRAINDICATIONS). No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Clinical Trials The efficacy of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray for the acute treatment of migraine headaches was evaluated in four randomized, double blind, placebo controlled studies in the U.S. The patient population for the trials was predominantly female (87%) and Caucasian (95%) with a mean age of 39 years (range 18 to 65 years). Patients treated a single moderate to severe migraine headache with a single dose of study medication and assessed pain severity over the 24 hours following treatment. Headache response was determined 0.5, 1, 2, 3 and 4 hours after dosing and was defined as a reduction in headache severity to mild or no pain. In studies 1 and 2, a four-point pain intensity scale was utilized; in studies 3 and 4, a five-point scale was used that included both pain response and restoration of function for “severe” or “incapacitating” pain, a less clear endpoint. Although rescue medication was allowed in all four studies, patients were instructed not to use them during the four hour observation period. In studies 3 and 4, a total dose of 2 mg was compared to placebo. In studies 1 and 2, doses of 2 and 3 mg were evaluated, and showed no advantage of the higher dose for a single treatment. In all studies, patients received a regimen consisting of 0.5 mg in each nostril, repeated in 15 minutes (and again in another 15 minutes for the 3 mg dose in studies 1 and 2). The percentage of patients achieving headache response 4 hours after treatment was significantly greater in patients receiving 2 mg doses of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray compared to those receiving placebo in 3 of the 4 studies (see Tables 1 & 2 and Figures 1 & 2). Table 1: Studies 1 and 2: Percentage of patients with headache responsea This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 4 2 and 4 hours following a single treatment of study medication [Migranal® (dihydroergotamine mesylate, USP) Nasal Spray or Placebo] N 2 hours 4 hours Study 1 Migranal® 105 61%* 70%** Placebo 98 23% 28% Study 2 Migranal® 103 47% 56%* Placebo 102 33% 35% aHeadache response was defined as a reduction in headache severity to mild or no pain. Headache response was based on pain intensity as interpreted by the patient using a four-point pain intensity scale. p value < 0.01 p value < 0.001 Table 2: Studies 3 and 4: Percentage of patients with headache responsea 2 and 4 hours following a single treatment of study medication [Migranal® (dihydroergotamine mesylate, USP) Nasal Spray or Placebo] N 2 hours 4 hours Study 3 Migranal® 50 32% 48% Placebo 50 20% 22% Study 4 Migranal® 47 30% 47% Placebo 50 20% 30% aHeadache response was defined as a reduction in headache severity to mild or no pain. Headache response was evaluated on a five-point scale that included both pain response and restoration of function for “severe” or “incapacitating” pain. p value < 0.01 Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study. The Kaplan-Meier plots below (Figures 1 & 2) provides an estimate of the probability that a patient will have responded to a single 2 mg dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray as a function of the time elapsed since initiation of treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 5 The figure shows the probability over time of obtaining a response following treatment with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Headache response was based on pain intensity as interpreted by the patient using a four-point pain intensity scale. Patients not achieving response within 4 hours were censored to 4 hours. The figure shows the probability over time of obtaining a response following treatment with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Headache response was evaluated on a five-point scale that confounded pain response and restoration of function for “severe” or “incapacitating” pain. Patients not achieving response within 4 hours were censored to 4 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 6 For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms at 2 and 4 hours following administration of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray compared to placebo. Patients were not allowed to use additional treatments for eight hours prior to study medication dosing and during the four hour observation period following study treatment. Following the 4 hour observation period, patients were allowed to use additional treatments. For all studies, the estimated probability of patients using additional treatments for their migraines over the 24 hours following the single 2 mg dose of study treatment is summarized in Figure 3 below. Kaplan-Meier plot based on data obtained from all studies with patients not using additional treatments censored to 24 hours. All patients received a single treatment of study medication for their migraine attack. The plot also includes patients who had no response to the initial dose. Neither age nor sex appear to effect the patient’s response to Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. While patients with menstrual migraine, migraine with aura, and migraine without aura by medical history were included in the clinical evaluation of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, patients were not required to report the specific type of migraine treated with study medication. Thus, neither the effect of menses on migraine nor the presence or the absence of aura were assessed. The racial distribution of patients was insufficient to determine the effect of race on the efficacy of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. INDICATIONS AND USAGE Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is indicated for the acute treatment of migraine headaches with or without aura. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is not intended for the prophylactic therapy of migraine or for the management of hemiplegic or basilar migraine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 7 CONTRAINDICATIONS There have been a few reports of serious adverse events associated with the coadministration of dihydroergotamine and potent CYP 3A4 inhibitors, such as protease inhibitors and macrolide antibiotics, resulting in vasospasm that led to cerebral ischemia and/or ischemia of the extremities. The use of potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole) with dihydroergotamine is, therefore contraindicated (See WARNINGS: CYP 3A4 Inhibitors). Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be given to patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have clinical symptoms or findings consistent with coronary artery vasospasm including Prinzmetal’s variant angina. (See WARNINGS) Because Migranal® (dihydroergotamine mesylate, USP) Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be administered to patients with hemiplegic or basilar migraine. In addition to those conditions mentioned above, Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery, and severely impaired hepatic or renal function. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray may cause fetal harm when administered to a pregnant woman. Dihydroergotamine possesses oxytocic properties and, therefore, should not be administered during pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. There are no adequate studies of dihydroergotamine in human pregnancy, but developmental toxicity has been demonstrated in experimental animals. In embryofetal development studies of dihydroergotamine mesylate nasal spray, intranasal administration to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weights and/or skeletal ossification at doses of 0.16 mg/day (associated with maternal plasma dihydroergotamine exposures [AUC] approximately 0.4 -1.2 times the exposures in humans receiving the MRDD of 4 mg) or greater. A no effect level for embryo-fetal toxicity was not established in rats. Delayed skeletal ossification was also noted in rabbit fetuses following intranasal administration of 3.6 mg/day (maternal exposures approximately 7 times human exposures at the MRDD) during organogenesis. A no effect level was seen at 1.2 mg/day (maternal exposures approximately 2.5 times human exposures at the MRDD). When dihydroergotamine mesylate nasal spray was administered intranasally to female rats during pregnancy and lactation, decreased body weights and impaired reproductive function (decreased mating indices) were observed in the offspring at doses of 0.16 mg/day or greater. A no effect level was not established. Effects on development occurred at doses below those that produced evidence of significant maternal toxicity in these studies. Dihydroergotamine-induced intrauterine growth retardation has been attributed to reduced uteroplacental blood flow resulting from prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 8 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids. Dihydroergotamine mesylate should not be used by nursing mothers. (See PRECAUTIONS) Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure. WARNINGS Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should only be used where a clear diagnosis of migraine headache has been established. CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of dihydroergotamine and potent CYP 3A4 inhibitors, such as protease inhibitors and macrolide antibiotics, resulting in vasospasm that led to cerebral ischemia and/or and ischemia of the extremities. The use of potent CYP 3A4 inhibitors with dihydroergotamine should therefore be avoided (see CONTRAINDICATIONS). Examples of some of the more potent CYP 3A4 inhibitors include: anti-fungals ketoconazole and itraconazole, the protease inhibitors ritonavir, nelfinavir, and indinavir, and macrolide antibiotics erythromycin, clarithromycin, and troleandomycin. Other less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP3A4 of other agents being considered for concomitant use with dihydroergotamine. Fibrotic Complications There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of injectable dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs has been associated with cardiac valvular fibrosis. Rare cases have also been reported in association with the use of injectable dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with cardiac valvular fibrosis. Administration of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION). Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be used by patients with documented ischemic or vasospastic coronary artery disease. (See CONTRAINDICATIONS) It is strongly recommended that Migranal® (dihydroergotamine mesylate, USP) Nasal Spray not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, females who are surgically or physiologically postmenopausal, or males who are over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 9 reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be administered. (See CONTRAINDICATIONS) For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received dihydroergotamine mesylate. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. The systematic approach described above is currently recommended as a method to identify patients in whom Migranal® (dihydroergotamine mesylate, USP) Nasal Spray may be used to treat migraine headaches with an acceptable margin of cardiovascular safety. Cardiac Events and Fatalities No deaths have been reported in patients using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. However, the potential for adverse cardiac events exists. Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported to have occurred following the administration of dihydroergotamine mesylate injection (e.g., D.H.E. 45® Injection). Considering the extent of use of dihydroergotamine mesylate in patients with migraine, the incidence of these events is extremely low. Drug-Associated Cerebrovascular Events and Fatalities Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with D.H.E. 45® Injection; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the D.H.E. 45® Injection having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 10 Other Vasospasm Related Events Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial and peripheral vascular ischemia have been reported with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray associated vasospastic phenomena may also cause muscle pains, numbness, coldness, pallor, and cyanosis of the digits. In patients with compromised circulation, persistent vasospasm may result in gangrene or death, Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should be discontinued immediately if signs or symptoms of vasoconstriction develop. Increase in Blood Pressure Significant elevation in blood pressure has been reported on rare occasions in patients with and without a history of hypertension treated with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray and dihydroergotamine mesylate injection. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is contraindicated in patients with uncontrolled hypertension. (See CONTRAINDICATIONS) An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5HT1 agonist in a study evaluating subjects undergoing cardiac catheterization. Local Irritation Approximately 30% of patients using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray (compared to 9% of placebo patients) have reported irritation in the nose, throat, and/or disturbances in taste. Irritative symptoms include congestion, burning sensation, dryness, paraesthesia, discharge, epistaxis, pain, or soreness. The symptoms were predominantly mild to moderate in severity and transient. In approximately 70% of the above mentioned cases, the symptoms resolved within four hours after dosing with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Examinations of the nose and throat in a small subset (N = 66) of study participants treated for up to 36 months (range 1-36 months) did not reveal any clinically noticeable injury. Other than this limited number of patients, the consequences of extended and repeated use of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray on the nasal and/or respiratory mucosa have not been systematically evaluated in patients. Nasal tissue in animals treated with dihydroergotamine mesylate daily at nasal cavity surface area exposures (in mg/mm2) that were equal to or less than those achieved in humans receiving the maximum recommended daily dose of 0.08 mg/kg/day showed mild mucosal irritation characterized by mucous cell and transitional cell hyperplasia and squamous cell metaplasia. Changes in rat nasal mucosa at 64 weeks were less severe than at 13 weeks. Local effects on respiratory tissue after chronic intranasal dosing in animals have not been evaluated. PRECAUTIONS General Migranal® (dihydroergotamine mesylate, USP) Nasal Spray may cause coronary artery vasospasm; patients who experience signs or symptoms suggestive of angina following its administration should, therefore, be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 11 Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud’s syndrome following the use of any 5-HT agonist are candidates for further evaluation. (See WARNINGS). Fibrotic Complications: see WARNINGS: Fibrotic Complications Information for Patients The text of a patient information sheet is printed at the end of this insert. To assure safe and effective use of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, the information and instructions provided in the patient information sheet should be discussed with patients. Once the nasal spray applicator has been prepared, it should be discarded (with any remaining drug) after 8 hours. Patients should be advised to report to the physician immediately any of the following: numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest, temporary speeding or slowing of the heart rate, swelling, or itching. Prior to the initial use of the product by a patient, the prescriber should take steps to ensure that the patient understands how to use the product as provided. (See Patient Information Sheet and product packaging). Administration of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION). Drug Interactions Vasoconstrictors Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure. Sumatriptan Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Sumatriptan and Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be taken within 24 hours of each other. (See CONTRAINDICATIONS) Beta Blockers Although the results of a clinical study did not indicate a safety problem associated with the administration of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray to subjects already receiving propranolol, there have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 12 Nicotine Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS. SSRI’s Weakness, hyperreflexia, and incoordination have been reported rarely when 5HT1 agonists have been co-administered with SSRI’s (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRI’s and Migranal® (dihydroergotamine mesylate, USP) Nasal Spray or D.H.E. 45®. Oral Contraceptives The effect of oral contraceptives on the pharmacokinetics of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray has not been studied. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing. Mutagenesis Dihydroergotamine mesylate was clastogenic in two in vitro chromosomal aberration assays, the V79 Chinese hamster cell assay with metabolic activation and the cultured human peripheral blood lymphocyte assay. There was no evidence of mutagenic potential when dihydroergotamine mesylate was tested in the presence or absence of metabolic activation in two gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay) and in an assay for DNA damage (the rat hepatocyte unscheduled DNA synthesis test). Dihydroergotamine was not clastogenic in the in vivo mouse and hamster micronucleus tests. Impairment of Fertility There was no evidence of impairment of fertility in rats given intranasal doses of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately 9 to 11 times those in humans receiving the MRDD of 4 mg). Pregnancy Pregnancy Category X. See CONTRAINDICATIONS. Nursing Mothers Ergot drugs are known to inhibit prolactin. It is likely that Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is excreted in human milk, but there are no data on the concentration of dihydroergotamine in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 13 human milk. It is known that ergotamine is excreted in breast milk and may cause vomiting, diarrhea, weak pulse, and unstable blood pressure in nursing infants. Because of the potential for these serious adverse events in nursing infants exposed to Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, nursing should not be undertaken with the use of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. (See CONTRAINDICATIONS) Pediatric Use Safety and effectiveness in pediatric patients have not been established. Use in the Elderly There is no information about the safety and effectiveness of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray in this population because patients over age 65 were excluded from the controlled clinical trials. ADVERSE REACTIONS During clinical studies and the foreign postmarketing experience with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray there have been no fatalities due to cardiac events. Serious cardiac events, including some that have been fatal, have occurred following use of the parenteral form of dihydroergotamine mesylate (D.H.E. 45® Injection), but are extremely rare. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate (see WARNINGS: Fibrotic Complications). Incidence in Controlled Clinical Trials Of the 1,796 patients and subjects treated with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray doses 2 mg or less in U.S. and foreign clinical studies, 26 (1.4%) discontinued because of adverse events. The adverse events associated with discontinuation were, in decreasing order of frequency: rhinitis 13, dizziness 2, facial edema 2, and one each due to cold sweats, accidental trauma, depression, elective surgery, somnolence, allergy, vomiting, hypotension, and paraesthesia. The most commonly reported adverse events associated with the use of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray during placebo-controlled, double-blind studies for the treatment of migraine headache and not reported at an equal incidence by placebo-treated patients were rhinitis, altered sense of taste, application site reactions, dizziness, nausea, and vomiting. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray was generally well tolerated. In most instances these events were transient and self-limited and did not result in patient discontinuation from a study. The following table summarizes the incidence rates of adverse events reported by at least 1% of patients who received Migranal® (dihydroergotamine mesylate, USP) Nasal Spray for the treatment of migraine headaches during placebo-controlled, double-blind clinical studies and were more frequent than in those patients receiving placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 14 Table 3: Adverse events reported by at least 1% of the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray treated patients and occurred more frequently than in the placebo-group in the migraine placebo-controlled trials Migranal® Placebo N=597 N=631 Respiratory System Rhinitis 26% 7% Pharyngitis 3% 1% Sinusitis 1% 1% Gastrointestinal System Nausea 10% 4% Vomiting 4% 1% Diarrhea 2% <1% Special Senses, Other Altered Sense of Taste 8% 1% Application Site Application Site Reaction 6% 2% Central and Peripheral Nervous System Dizziness 4% 2% Somnolence 3% 2% Paraesthesia 2% 2% Body as a Whole, General Hot Flushes 1% <1% Fatigue 1% 1% Asthenia 1% 0% Autonomic Nervous System Mouth Dry 1% 1% Musculoskeletal System Stiffness 1% <1% Other Adverse Events During Clinical Trials In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used Migranal® (dihydroergotamine mesylate, USP) Nasal Spray in placebo-controlled trials and reported an event divided by the total number of patients (n=1796) exposed to Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; and rare adverse events are those occurring in fewer than 1/1,000 patients. Skin and Appendages: Infrequent: petechia, pruritus, rash, cold clammy skin; Rare: papular rash, urticaria, herpes simplex. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 15 Musculoskeletal: Infrequent: cramps, myalgia, muscular weakness, dystonia; Rare: arthralgia, involuntary muscle contractions, rigidity. Central and Peripheral Nervous System: Infrequent: confusion, tremor, hypoesthesia, vertigo; Rare: speech disorder, hyperkinesia, stupor, abnormal gait, aggravated migraine. Autonomic Nervous System: Infrequent: increased sweating. Special Senses: Infrequent: sense of smell altered, photophobia, conjunctivitis, abnormal lacrimation, abnormal vision, tinnitus, earache; Rare: eye pain. Psychiatric: Infrequent: nervousness, euphoria, insomnia, concentration impaired; Rare: anxiety, anorexia, depression. Gastrointestinal: Infrequent: abdominal pain, dyspepsia, dysphagia, hiccup; Rare: increased salivation, esophagospasm. Cardiovascular: Infrequent: edema, palpitation, tachycardia; Rare: hypotension, peripheral ischemia, angina. Respiratory System: Infrequent: dyspnea, upper respiratory tract infections; Rare: bronchospasm, bronchitis, pleural pain, epistaxis. Urinary System: Infrequent: increased frequency of micturition, cystitis. Reproductive, Female: Rare: pelvic inflammation, vaginitis. Body as a Whole - General: Infrequent: feeling cold, malaise, rigors, fever, periorbital edema; Rare: flu-like symptoms, shock, loss of voice, yawning. Application Site: Infrequent: local anesthesia. Post-introduction Reports Voluntary reports of adverse events temporally associated with dihydroergotamine products used in the management of migraine that have been received since the introduction of the injectable formulation are included in this section save for those already listed above. Because of their source (open and uncontrolled clinical use), whether or not events reported in association with the use of dihydroergotamine are causally related to it cannot be determined. There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of injectable dihydroergotamine mesylate. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is not recommended for prolonged daily use. (See DOSAGE AND ADMINISTRATION) DRUG ABUSE AND DEPENDENCE Currently available data have not demonstrated drug abuse or psychological dependence with dihydroergotamine. However, cases of drug abuse and psychological dependence in patients on other forms of ergot therapy have been reported. Thus, due to the chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages. OVERDOSAGE To date, there have been no reports of acute overdosage with this drug. Due to the risk of vascular spasm, exceeding the recommended dosages of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is to be avoided. Excessive doses of dihydroergotamine may result in peripheral signs and symptoms of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 16 ergotism. Treatment includes discontinuance of the drug, local application of warmth to the affected area, the administration of vasodilators, and nursing care to prevent tissue damage. In general, the symptoms of an acute Migranal® (dihydroergotamine mesylate, USP) Nasal Spray overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. The symptoms of an ergotamine overdose include the following: numbness, tingling, pain, and cyanosis of the extremities associated with diminished or absent peripheral pulses; respiratory depression; an increase and/or decrease in blood pressure, usually in that order; confusion, delirium, convulsions, and coma; and/or some degree of nausea, vomiting, and abdominal pain. In laboratory animals, significant lethality occurs when dihydroergotamine is given at I.V. doses of 44 mg/kg in mice, 130 mg/kg in rats, and 37 mg/kg in rabbits. Up-to-date information about the treatment of overdosage can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians’ Desk Reference® (PDR).* DOSAGE AND ADMINISTRATION The solution used in Migranal® (dihydroergotamine mesylate, USP) Nasal Spray (4 mg/mL) is intended for intranasal use and must not be injected. In clinical trials, Migranal® (dihydroergotamine mesylate, USP) Nasal Spray has been effective for the acute treatment of migraine headaches with or without aura. One spray (0.5 mg) of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should be administered in each nostril. Fifteen minutes later, an additional one spray (0.5 mg) of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should be administered in each nostril, for a total dosage of four sprays (2.0 mg) of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Studies have shown no additional benefit from acute doses greater than 2.0 mg for a single migraine administration. The safety of doses greater than 3.0 mg in a 24 hour period and 4.0 mg in a 7 day period has not been established. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, should not be used for chronic daily administration. Prior to administration, the pump must be primed (i.e., squeeze 4 times) before use. (See Patient Information Sheet or Patient Instruction Booklet) Once the nasal spray applicator has been prepared, it should be discarded (with any remaining drug in opened ampul) after 8 hours. HOW SUPPLIED Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is available (as a clear, colorless to faintly yellow solution) in 1 mL amber glass ampuls containing 4 mg of dihydroergotamine mesylate, USP (NDC 0078-0245-98). Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is provided in individual kits. The kits consist of four unit dose trays, a patient instruction booklet, one assembly case, and one patient information sheet packed in a carton. Each unit dose tray contains one ampul, a nasal spray applicator, and a breaker cap on the ampul. Store below 77°F (25°C). Do not refrigerate or freeze. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 17 Patient Information Information for the Patient Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. The solution used in Migranal® (dihydroergotamine mesylate, USP) Nasal Spray (4 mg/mL) is intended for intranasal use and must not be injected. Please read this information carefully before using your Migranal® (dihydroergotamine mesylate, USP) Nasal Spray for the first time. Keep this information handy for future reference. This leaflet does not contain all of the information on Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Your pharmacist and/or health care provider can provide more detailed information. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray has been evaluated in a limited number of patients long term (e.g., 1 year or longer). Purpose of your Medication Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is intended to treat an active migraine headache. Do not try to use it to prevent a headache if you have no symptoms. Do not use it to treat common tension headache or a headache that is not at all typical of your usual migraine headache. Administration of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration. There have been reports of fibrosis (stiffening) in the lung or kidney areas in patients following prolonged daily use of injectable dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs (the class of drugs to which Migranal® (dihydroergotamine mesylate, USP) Nasal Spray belongs) has been associated with heart valvular fibrosis. Rare cases have also been reported in association with the use of injectable dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with heart valvular fibrosis. Do not use Migranal® (dihydroergotamine mesylate, USP) Nasal Spray if you: • are pregnant or nursing. • have any disease affecting your heart, arteries, or circulation. • are taking certain anti-HIV medications (protease inhibitors). • are taking a macrolide antibiotic such as troleandomycin, clarithromycin or erythromycin. Important questions to consider before using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray Please answer the following questions before you use your Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. If you answer YES to any of these questions or are unsure of the answer, you should talk to your doctor before using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. • Do you have high blood pressure? • Do you have chest pain, shortness of breath, heart disease, or have you had any surgery on your heart arteries? This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 18 • Do you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal or a male over 40)? • Do you have any problems with blood circulation in your arms or legs, fingers, or toes? • Are you pregnant? Do you think you might be pregnant? Are you trying to become pregnant? Are you sexually active and not using birth control? Are you breast feeding? • Have you ever had to stop taking this or any other medication because of an allergy or bad reaction? • Are you taking any other migraine medications, erythromycin or other antibiotics, or medications for blood pressure prescribed by your doctor, or other medicines obtained from your drugstore without a doctor’s prescription? • Do you smoke? • Have you had, or do you have, any disease of the liver or kidney? • Is this headache different from your usual migraine attacks? • Are you using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray or other dihydroergotamine mesylate containing drugs on a daily basis? • Are you taking a protease inhibitor for HIV therapy? • Are you taking a macrolide class of antibiotic? Serious or potentially life-threatening reductions in blood flow to the brain or extremities have been reported rarely due to interactions between Migranal® (dihydroergotamine mesylate, USP) Nasal Spray and protease inhibitors or macrolide antibiotics. REMEMBER TO TELL YOUR DOCTOR IF YOU HAVE ANSWERED YES TO ANY OF THESE QUESTIONS BEFORE YOU USE MIGRANAL® (dihydroergotamine mesylate, USP) NASAL SPRAY. Side Effects To Watch Out For In clinical trials, most migraine patients have used Migranal® (dihydroergotamine mesylate, USP) Nasal Spray without serious side effects. You may experience some nasal congestion or irritation, altered sense of taste, sore throat, nausea, vomiting, dizziness, and fatigue after using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. These side effects are temporary and usually do not require you to stop using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Although the following reactions rarely occur, they can be serious and should be reported to your physician immediately: • Numbness or tingling in your fingers and toes • Pain, tightness, or discomfort in your chest • Muscle pain or cramps in your arms and legs • Weakness in your legs • Temporary speeding or slowing of your heart rate • Swelling or itching This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 19 Dosing Information • Each ampul contains one complete dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, which is 1 spray in each nostril followed in 15 minutes by an additional spray in each nostril, for a total of 4 sprays. • Studies have shown no benefit from acute doses greater than 2.0 mg (4 sprays) for a single administration. The safety of doses greater than 3.0 mg in a 24 hour period has not been established. • The safety of doses greater than 4.0 mg in a 7-day period has not been established. • Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, should not be used for chronic daily administration. Learn what to do in case of an Overdose If you have used more medication than you have been instructed, contact your doctor, hospital emergency department, or nearest poison control center immediately. How to use the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray 1. Use available training materials. • Read and follow the instructions in the patient instruction booklet which is provided with the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray package before attempting to use the product. • If there are any questions concerning the use of your Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, ask your doctor or pharmacist, or call the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray Information Line at 1-888-MY-RELIEF (1-888-697-3543) for training in the use of the spray. 2. Check the contents of the package. • Assembly Case • Well (which is part of the Assembly Case) • Unit Dose Tray • Brown (amber) glass ampul with yellow breaker cap • Nasal Sprayer with cover 3. Assemble the sprayer. Assemble your Nasal Sprayer only when you are ready to use it. • Tap top of ampul until all medication is in the bottom. • Place ampul upright and straight in well of the Assembly Case with breaker cap pointing up. • Push down the Assembly Case lid slowly but firmly, until you hear ampul snap open. • Without removing ampul from well, push Nasal Sprayer onto ampul until it clicks. (To ensure that the ampul fits properly into the Nasal Sprayer, first look at the tube through the bottom of sprayer to make sure it is straight. If it is curved, straighten it with your finger.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 20 4. Using the sprayer: • Remove cover from the Nasal Sprayer. • Pump the Nasal Sprayer 4 times before using. (Point the Nasal Sprayer up and away from your face when pumping.) Do not prime the Nasal Sprayer more than 4 times. Although some medication will spray out, there is enough medication in each ampul to allow you to prepare your sprayer properly and still receive a full dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. • Spray once in each nostril. You should not tilt head back or inhale through your nose while spraying. • Wait 15 minutes, then spray once in each nostril again. 5. After completing these instructions: • Carefully dispose of the Nasal Sprayer containing the ampul and the breaker cap containing the top of the ampul. • Load a new Unit Dose Tray into your Assembly Case. • Keep the Assembly Case for a maximum of 4 treatments, then discard it along with the Unit Dose Tray. Important Notes: • Once a Migranal® (dihydroergotamine mesylate, USP) Nasal Spray ampul has been opened, it must be thrown away after 8 hours. • You should not sniff or tilt your head back when using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Storing Migranal® (dihydroergotamine mesylate, USP) Nasal Spray • Keep medication in a safe place away from children. • Keep Migranal® (dihydroergotamine mesylate, USP) Nasal Spray away from heat and light. – Do not expose Migranal® (dihydroergotamine mesylate, USP) Nasal Spray to temperatures over 77°F. – Never refrigerate or freeze Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. • Keep Migranal® (dihydroergotamine mesylate, USP) Nasal Spray components in the Unit Dose Tray. • Keep the Unit Dose Tray loaded in the Assembly Case. • Do not keep an opened Migranal® (dihydroergotamine mesylate, USP) Nasal Spray ampul for more than 8 hours. Check the expiration date printed on the ampul containing medication. If the expiration date has passed, do not use it. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 21 Answers to patients’ questions about Migranal® (dihydroergotamine mesylate, USP) Nasal Spray What if I need help in using my Migranal® (dihydroergotamine mesylate, USP) Nasal Spray? If you have any questions or if you need help in opening, putting together, or using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, speak to your doctor or pharmacist, or call the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray Information Line at 1-888-MY-RELIEF (1-888-697-3543). How much medication should I use and how often? Each ampul contains one complete dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, which is 1 spray in each nostril, followed by an additional spray in each nostril 15 minutes later for a total of 4 sprays. Do not use more than this amount unless instructed to do so by your doctor. Why do I have to prime or pump the Nasal Sprayer 4 times before using? Am I wasting the medication? You have to prime the Nasal Sprayer 4 times to make sure that you get the proper amount of medication when you use it. Although you will see some medication spray out, there is still enough medication in each ampul to allow you to prepare your sprayer properly and still receive a full dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Can I load the medication ampul into the Nasal Sprayer so it is ready before I need to use it? No. The brown (amber) glass ampul containing your medication must remain unopened until you are ready to use it. It may not be fully effective if opened and not used within 8 hours. However, after each migraine attack, you should load a new plastic Unit Dose Tray containing an unopened Migranal® (dihydroergotamine mesylate, USP) Nasal Spray ampul and Nasal Sprayer into the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray Assembly Case, so you will be prepared for your next migraine attack. Can I reuse my Migranal® (dihydroergotamine mesylate, USP) Nasal Sprayer? No. After completing the full dose, you must carefully dispose of your Migranal® (dihydroergotamine mesylate, USP) Nasal Sprayer containing the opened ampul. Each Unit Dose Tray contains a new Nasal Sprayer, an ampul of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray medication, and a breaker cap on the ampul. But you should keep your Assembly Case and load it with a new Unit Dose Tray after each migraine so you are ready to treat your next migraine attack. Can I use Migranal® (dihydroergotamine mesylate, USP) Nasal Spray if I have a stuffy nose, cold, or allergies? Yes. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray can be used if you have a stuffy nose, cold, or allergies. However, if you are taking any medications for your cold, or allergies, even those you can buy without a doctor’s prescription, speak with your doctor before using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda N 20-148/ S-007 S-008 Package Insert Page 22 Do I need to sniff the medication when I spray it in my nostril? No, you should not sniff because Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should remain in the nose so that it can be absorbed into the bloodstream through the lining of the nose. If you have any other unanswered question about Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, consult your doctor or pharmacist. *Trademark of Medical Economics Company, Inc. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Russell Katz 7/31/02 09:15:34 AM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:49.665634	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20148s7s8lbl.pdf', 'application_number': 20148, 'submission_type': 'SUPPL ', 'submission_number': 7}
12,251	Effexor Relapse/Recurrence CONFIDENTIAL 1 16 Mar 01 Effexor  (venlafaxine hydrochloride) Tablets DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. •HCl H3CO H C OH N (CH3)2 venlafaxine hydrochloride Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 2 16 Mar 01 the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27%±2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30%±12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half- life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; elimination half-life is 5±2 and 11±2 hours, respectively; and steady- state volume of distribution is 7.5±3.7 L/kg and 5.7±1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see “DOSAGE AND ADMINISTRATION”). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 3 16 Mar 01 Liver Disease In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic patients compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. Dosage adjustment is necessary in these patients (see “DOSAGE AND ADMINISTRATION”). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see “DOSAGE AND ADMINISTRATION”). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for depression was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression—Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 4 16 Mar 01 dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤ 3 and a HAM-D-21 total score of ≤ 10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥ 4 (moderately ill), or (2) 2 consecutive CGI Severity of Illness item scores of ≥ 4, or (3) a final CGI Severity of Illness item score of ≥ 4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤ 12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥ 20, (2) no more than 2 HAM-D-21 total scores > 10, and (3) no single CGI Severity of Illness item score ≥ 4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100-200 mg/day, on a bid schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥ 4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of depression. The efficacy of Effexor in the treatment of depression was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 5 16 Mar 01 of major depressive disorder and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depressive disorder with melancholia (see “CLINICAL TRIALS”). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see “CLINICAL TRIALS”). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Effexor (venlafaxine hydrochloride) is contraindicated in patients known to be hypersensitive to it. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see “WARNINGS”). WARNINGS Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on Effexor, or who have recently had Effexor therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with a monoamine oxidase inhibitor, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 6 16 Mar 01 include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. Therefore, it is recommended that Effexor not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Effexor, at least 7 days should be allowed after stopping Effexor before starting an MAOI. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP $90 mm Hg and $10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine: Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10-15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. PRECAUTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 7 16 Mar 01 General Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short- term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety 6% 3% Nervousness 13% 6% Insomnia 18% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the phase 2–3 depression studies. Changes in Appetite and Weight Treatment-emergent anorexia was more commonly reported for venlafaxine-treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. A dose-dependent weight loss was often noted in patients treated with venlafaxine for several weeks. Significant weight loss, especially in underweight depressed patients, may be an undesirable result of venlafaxine treatment. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the phase 2-3 depression trials). Activation of Mania/Hypomania During phase 2-3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intra- ocular pressure or at risk of acute narrow angle glaucoma should be monitored. Seizures This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 8 16 Mar 01 During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Suicide The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo- controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor-treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo- controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The clinical significance of these changes is unknown. In patients with renal impairment (GFR=10-70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see “DOSAGE AND ADMINISTRATION”). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 9 16 Mar 01 Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. Information for Patients Physicians are advised to discuss the following issues with patients for whom they prescribe Effexor: Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 10 16 Mar 01 Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (CI/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O- desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 11 16 Mar 01 pharmacokinetics of lithium. Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 12 16 Mar 01 Imipramine— Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH- imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC’s increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH- desipramine levels is unknown. Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir— In a study of 9 healthy volunteers, venlafaxine administered under steady- state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. The clinical significance of this finding is unknown. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see “Diazepam” above). Monoamine Oxidase Inhibitors See “CONTRAINDICATIONS” and “WARNINGS.” CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 13 16 Mar 01 Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. Postmarketing Spontaneous Drug Interaction Reports See “ADVERSE REACTIONS, Postmarketing Reports.” Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis. Pregnancy Teratogenic Effects—Pregnancy Category C This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 14 16 Mar 01 Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Usage in Children Safety and effectiveness in individuals below 18 years of age have not been established. Geriatric Use Of the 2,897 patients in phase 2-3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see “CLINICAL PHARMACOLOGY”). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 15 16 Mar 01 the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see “DOSAGE AND ADMINISTRATION”). ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in phase 2-3 depression studies discontinued treatment due to an adverse event. The more common events (≥ 1%) associated with discontinuation and considered to be drug-related (i.e., those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: CNS Venlafaxine Placebo Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% — Nervousness 2% — Dry mouth 2% — Anxiety 2% 1% Gastrointestinal Nausea 6% 1% Urogenital Abnormal ejaculation* 3% — Other Headache 3% 1% Asthenia 2% — Sweating 2% — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 16 16 Mar 01 range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. TABLE 1 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Body as a Whole Headache 25% 24% Asthenia 12% 6% Infection 6% 5% Chills 3% — Chest pain 2% 1% Trauma 2% 1% Cardiovascular Vasodilatation 4% 3% Increased blood pressure/hypertension 2% — Tachycardia 2% — Postural hypotension 1% — Dermatological Sweating 12% 3% Rash 3% 2% Pruritus 1% — This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 17 16 Mar 01 Gastrointestinal Nausea 37% 11% Constipation 15% 7% Anorexia 11% 2% Diarrhea 8% 7% Vomiting 6% 2% Dyspepsia 5% 4% Flatulence 3% 2% Metabolic Weight loss 1% — Nervous System Somnolence 23% 9% Dry mouth 22% 11% Dizziness 19% 7% Insomnia 18% 10% Nervousness 13% 6% Anxiety 6% 3% Tremor 5% 1% Abnormal dreams 4% 3% Hypertonia 3% 2% Paresthesia 3% 2% Libido decreased 2% — Agitation 2% — Confusion 2% 1% Thinking abnormal 2% 1% Depersonalization 1% — Depression 1% — Urinary retention 1% — Twitching 1% — Respiration Yawn 3% — Special Senses Blurred vision 6% 2% Taste perversion 2% — Tinnitus 2% — Mydriasis 2% — Urogenital System Abnormal ejaculation/ Orgasm 12%2 —2 Impotence 6%2 —2 Urinary frequency 3% 2% Urination impaired 2% —3 Orgasm disturbance 2%3 —3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 18 16 Mar 01 Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose- dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. TABLE 2 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo 75 225 375 (n=92) (n=89) (n=89) (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% Cardiovascular System Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 19 16 Mar 01 Special Senses Abnormality of 0.0% 9.1% 7.9% 5.6% Accommodation Urogenital System Abnormal Ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% (Number of men) (n=63) (n=52) (n=48) (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., dizziness and nausea), but less to other effects (e.g., abnormal ejaculation and dry mouth). Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. It was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see “WARNINGS”). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol, i.e., patients treated with Effexor had mean increases from baseline of 3 mg/dL, a change of unknown clinical significance. ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, i.e., a mean increase from baseline of 4 beats per minute for Effexor (see “PRECAUTIONS, General, Use in Patients with Concomitant Illness”). Other Events Observed during the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in phase 2 and 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in phase 3 depression studies and Effexor was administered to 96 patients. During its premarketing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 20 16 Mar 01 assessment for Generalized Anxiety Disorder, multiple doses of Effexor XR were administered to 476 patients in phase 3 studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double- blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 4174 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 1 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole - Frequent: chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt; Rare: appendicitis, bacteremia, carcinoma, cellulitis, withdrawal syndrome. Cardiovascular system - Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mitral valve disorder, mucocutaneous hemorrhage, myocardial infarct, pallor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 21 16 Mar 01 Digestive system - Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, oral moniliasis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system - Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, glycosuria, hypercholesteremia, hyperglycemia, hyperuricemia, hypoglycemia, hypokalemia, SGOT increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, dehydration, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperlipemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia SGPT increased, uremia. Musculoskeletal system - Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, rheumatoid arthritis, tendon rupture. Nervous system - Frequent: emotional lability, trismus, vertigo; Infrequent: apathy, ataxia, circumoral paresthesia, CNS stimulation, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, paranoid reaction, psychosis, seizure, abnormal speech, stupor; Rare: akathisia, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain- Barre Syndrome, hypokinesia, neuritis, nystagmus, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system - Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larnyx edema, pleurisy, pulmonary embolus, sleep apnea. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 22 16 Mar 01 Skin and appendages - Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythremia nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses - Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, exophthalmos, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system - Frequent: metrorrhagia,* prostatitis,* vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, female lactation,* leukorrhea,* menorrhagia,* nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, breast discharge, breast engorgement, breast enlargement, endometriosis,* fibrocystic breast, calcium crystalluria, cervicitis,* ovarian cyst,* prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm.* Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of Effexor that have been received since market introduction and that may have no causal relationship with the use of Effexor include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities (such as atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, ventricular tachycardia), epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including tardive dyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), pancreatitis, panic, prolactin increased, renal failure, serotonin syndrome, shock-like electrical sensations (in some cases, subsequent to the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 23 16 Mar 01 discontinuation of Effexor or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. While the discontinuation effects of Effexor have not been systematically evaluated in controlled clinical trials, a retrospective survey of new events occurring during taper or following discontinuation revealed the following six events that occurred at an incidence of at least 5% and for which the incidence for Effexor was at least twice the placebo incidence: asthenia, dizziness, headache, insomnia, nausea, and nervousness. Therefore, it is recommended that the dosage be tapered gradually and the patient monitored (see “DOSAGE AND ADMINISTRATION”). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (e.g., development of tolerance, incrementation of dose, drug- seeking behavior). OVERDOSAGE Human Experience This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 24 16 Mar 01 There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 µg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), seizures, vertigo, and death have been reported. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 25 16 Mar 01 DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared to normal subjects (see “CLINICAL PHARMACOLOGY”), it is recommended that the total daily dose be reduced by 50% in patients with moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10-70 mL/min) compared to normals (see “CLINICAL PHARMACOLOGY”), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% and the dose be withheld until the dialysis treatment is completed (4 hrs) in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 26 16 Mar 01 It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for a period of up to 52 weeks on the same dose (100-200 mg/day, on a bid schedule) (see “CLINICAL TRIALS”). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Discontinuing Effexor (venlafaxine hydrochloride) When discontinuing Effexor after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. Patients who have received Effexor for 6 weeks or more should have their dose tapered gradually over a 2-week period. SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see “CONTRAINDICATIONS” and “WARNINGS”). HOW SUPPLIED Effexor® (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “ reverse side. NDC 0008-0701-01, bottle of 100 tablets. NDC 0008-0701-02, carton of 10 Redipak® blister strips of 10 tablets each. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “ ” on one side and “781” on scored reverse side. NDC 0008-0781-01, bottle of 100 tablets. NDC 0008-0781-02, carton of 10 Redipak® blister strips of 10 tablets each. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor Relapse/Recurrence CONFIDENTIAL 27 16 Mar 01 50 mg, peach, shield-shaped tablet with “50” and a “ ” on one side and “703” on scored reverse side. NDC 0008-0703-01, bottle of 100 tablets. NDC 0008-0703-02, carton of 10 Redipak® blister strips of 10 tablets each. 75 mg, peach, shield-shaped tablet with “75” and a “ ” on one side and “704” on scored reverse side. NDC 0008-0704-01, bottle of 100 tablets. NDC 0008-0704-02, carton of 10 Redipak® blister strips of 10 tablets each. 100 mg, peach, shield-shaped tablet with “100” and a “ ” on one side and “705” on scored reverse side. NDC 0008-0705-01, bottle of 100 tablets. NDC 0008-0705-02, carton of 10 Redipak® blister strips of 10 tablets each. The appearance of these tablets is a trademark of Wyeth-Ayerst Laboratories. Store at controlled room temperature, 20ºC to 25ºC (68ºF to 77ºF), in a dry place. Dispense in a well-closed container as defined in the USP. [Wyeth logo] Based on CI 6027- 2 Revised January 12, 2000 Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 1 16 Mar 01 Effexor® XR (venlafaxine hydrochloride) Extended-Release Capsules DESCRIPTION Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. Venlafaxine hydrochloride is chemically unrelated to tricyclic, tetracyclic, or other available antidepressants and to other agents used to treat Generalized Anxiety Disorder. It is designated (R/S)-1-[2-(dimethylamino)-1-(4- methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p- methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 hydrochloride. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Effexor XR is formulated as an extended-release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, and titanium dioxide. The 37.5 mg capsule also contains D&C Red #28, D&C Yellow #10, and FD&C Blue #1. •HCl H3CO H C OH N (CH3)2 venlafaxine hydrochloride This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 2 16 Mar 01 CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27 and 30%, respectively). Absorption Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for immediate release venlafaxine tablets (Cmax’s for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax’s were 2 hours for venlafaxine and 3 hours for ODV). When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 3 16 Mar 01 slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. Metabolism and Excretion Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion. Special Populations Age and Gender: A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary (see “DOSAGE AND ADMINISTRATION”). Extensive/Poor Metabolizers: Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups. Liver Disease: In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 4 16 Mar 01 Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic patients compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. Dosage adjustment is necessary in these patients (see “DOSAGE AND ADMINISTRATION”). Renal Disease: In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see “DOSAGE AND ADMINISTRATION”). Clinical Trials Depression The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for depression was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depression. A 12-week study utilizing Effexor XR doses in a range 75-150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75-225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Effexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, Effexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score. A 4-week study of inpatients meeting DSM-III-R criteria for major depression with melancholia utilizing Effexor (the immediate release form of venlafaxine) in a range of 150 to 375 mg/day This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 5 16 Mar 01 (t.i.d. schedule) demonstrated superiority of Effexor over placebo. The mean dose in completers was 350 mg/day. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. In one longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤ 3 and a HAM-D-21 total score of ≤ 10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥ 4 (moderately ill), or (2) 2 consecutive CGI Severity of Illness item scores of ≥ 4, or (3) a final CGI Severity of Illness item score of ≥ 4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤ 12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥ 20, (2) no more than 2 HAM-D-21 total scores > 10, and (3) no single CGI sSeverity of Illness item score ≥ 4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100-200 mg/day, on a bid schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥ 4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. Generalized Anxiety Disorder The efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month, placebo- controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in outpatients meeting DSM-IV criteria for GAD. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 6 16 Mar 01 One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose. A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes, however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-response relationship for effectiveness in GAD was not clearly established in the 75-225 mg/day dose range utilized in these two studies. Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and the other evaluating Effexor XR doses of 75-225 mg/day, showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. INDICATIONS AND USAGE Depression Effexor XR (venlafaxine hydrochloride) extended-release capsules is indicated for the treatment of depression. The efficacy of Effexor XR in the treatment of depression was established in 8- and 12-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see “Clinical Trials”). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 7 16 Mar 01 The efficacy of Effexor (the immediate release form of venlafaxine) in the treatment of depression in inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see “Clinical Trials”). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see “Clinical Trials”). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Generalized Anxiety Disorder Effexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in outpatients diagnosed with GAD according to DSM-IV criteria (See “Clinical Trials”). Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (See “DOSAGE AND ADMINISTRATION”). CONTRAINDICATIONS Effexor XR (venlafaxine hydrochloride) extended-release capsules is contraindicated in patients known to be hypersensitive to venlafaxine hydrochloride. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 8 16 Mar 01 Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see "WARNINGS"). WARNINGS Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it is recommended that Effexor XR (venlafaxine hydrochloride) extended-release capsules not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI. Sustained Hypertension Venlafaxine is associated with sustained increases in blood pressure in some patients. Among patients treated with 75-375 mg per day of Effexor XR in premarketing depression studies, 3% (19/705) experienced sustained hypertension [defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive on-therapy visits]. Among patients treated with 37.5-225 mg per day of Effexor XR in premarketing GAD studies, 0.5% (5/1011) experienced sustained hypertension. Experience with the immediate- release venlafaxine showed that sustained hypertension was dose-related, increasing from 3-7% at This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 9 16 Mar 01 100-300 mg per day to 13% at doses above 300 mg per day. An insufficient number of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. In placebo-controlled premarketing depression studies with Effexor XR 75-225 mg/day, a final on-drug mean increase in supine diastolic blood pressure (SDBP) of 1.2 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.2 mm Hg for placebo-treated patients. In placebo-controlled premarketing GAD studies with Effexor XR 37.5-225 mg/day up to 8 weeks or up to 6 months, a final on-drug mean increase in SDBP of 0.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.9 and 0.8 mm Hg, respectively, for placebo-treated patients. In premarketing depression studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12-16 mm Hg, SDBP) In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12-25 mm Hg, SDBP up to 8 weeks; 8-28 mm Hg up to 6 months). Sustained increases of SDBP could have adverse consequences. Therefore, it is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 10 16 Mar 01 PRECAUTIONS General Insomnia and Nervousness Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term depression and GAD studies, as shown in Table 1. Table 1 Incidence of Insomnia and Nervousness in Placebo-Controlled Depression and GAD Trials Depression GAD Symptom Effexor XR n = 357 Placebo n = 285 Effexor XR n = 1381 Placebo n = 555 Insomnia 17% 11% 15% 10% Nervousness 10% 5% 6% 4% Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in Phase 3 depression studies. In Phase 3 GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with Effexor XR up to 6 months. Changes in Appetite and Weight Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (4%) in the pool of short-term depression studies. Significant weight loss, especially in underweight depressed patients, may be an undesirable result of Effexor XR treatment. A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in placebo-controlled depression trials. Discontinuation rates for anorexia and weight loss associated with Effexor XR were low (1.0% and 0.1%, respectively, of Effexor XR-treated patients in Phase 3 depression studies). In the pool of GAD studies, treatment-emergent anorexia was reported in 8% and 2% of patients receiving Effexor XR and placebo up to 8 weeks, respectively. A loss of 7% or more of body weight occurred in 3% of the Effexor XR-treated and 1% of the placebo-treated patients up to 6 months in these trials. Discontinuation rates for anorexia and weight loss were low for patients receiving Effexor XR up to 8 weeks (0.9% and 0.3% respectively). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 11 16 Mar 01 Activation of Mania/Hypomania During premarketing depression studies, mania or hypomania occurred in 0.3% of Effexor XR- treated patients and 0.0% placebo patients. In premarketing GAD studies, 0.0% of Effexor XR- treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In all premarketing depression trials with Effexor, mania or hypomania occurred in 0.5% of venlafaxine- treated patients compared with 0% of placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed antidepressants. As with all antidepressants, Effexor XR should be used cautiously in patients with a history of mania. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow-angle glaucoma should be monitored. Seizures During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the depression studies or among 1381 Effexor XR-treated patients in GAD studies. In all premarketing depression trials with Effexor, seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures. Suicide The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management in order to reduce the risk of overdose. The same precautions observed when treating patients with depression should be observed when treating patients with GAD. Use in Patients With Concomitant Illness Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor XR to patients with diseases or conditions that could affect hemodynamic responses or metabolism. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 12 16 Mar 01 Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms for 357 patients who received Effexor XR and 285 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in depression and the electrocardiograms for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in depression studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). The clinical significance of these changes is unknown. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the depression studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and no change for placebo). The clinical significance of these changes is unknown. Evaluation of the electrocardiograms for 769 patients who received immediate release Effexor in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. In patients with renal impairment (GFR=10-70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see “DOSAGE AND ADMINISTRATION”). Effexor XR, like all antidepressants, should be used with caution in such patients. Information for Patients Physicians are advised to discuss the following issues with patients for whom they prescribe Effexor XR (venlafaxine hydrochloride) extended-release capsules: Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 13 16 Mar 01 cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities. Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O- desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 14 16 Mar 01 Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium. Drugs Highly Bound to Plasma Proteins Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 15 16 Mar 01 Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (See “Metabolism and Excretion” under “CLINICAL PHARMACOLOGY”). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce simultaneous inhibition of these two enzymes systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH- imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC’s increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH- desipramine levels is unknown. Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 16 16 Mar 01 CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir— In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg per day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. The clinical significance of this finding is unknown. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see “Diazepam” above.) Monoamine Oxidase Inhibitors See “CONTRAINDICATIONS” and “WARNINGS”. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment. Postmarketing Spontaneous Drug Interaction Reports See “ADVERSE REACTIONS,” “Postmarketing Reports.” This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 17 16 Mar 01 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenesis Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also was not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose on a mg/m2 basis. Pregnancy Teratogenic Effects - Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 18 16 Mar 01 Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Approximately 4% (14/357) and 6% (77/1381) of Effexor XR-treated patients in placebo- controlled premarketing depression and GAD trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated patients in premarketing phase depression studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see “CLINICAL PHARMACOLOGY”). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see “DOSAGE AND ADMINISTRATION”). ADVERSE REACTIONS The information included in the Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three 8- and 12-week controlled clinical trials in depression (includes two U.S. trials and one European trial) and on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR. Information on additional adverse events associated with Effexor XR in the entire development program for the formulation and with Effexor (the immediate release formulation of venlafaxine) is This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 19 16 Mar 01 included in the “Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR” subsection (See also “WARNINGS” and “PRECAUTIONS”). Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR Adverse Events Associated with Discontinuation of Treatment Approximately 11% of the 357 patients who received Effexor XR (venlafaxine hydrochloride) extended-release capsules in placebo-controlled clinical trials for depression discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. The most common events leading to discontinuation and considered drug-related (i.e., leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for either indication) are shown in Table 2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 20 16 Mar 01 Table 2 Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials1 Percentage of Patients Discontinuing Due to Adverse Event Adverse Event Depression Indication2 GAD Indication3,4 Effexor XR n=357 Placebo n=285 Effexor XR n=1381 Placebo n=555 Body as a Whole Asthenia -- -- 3% <1% Digestive System Nausea 4% <1% 8% <1% Anorexia 1% <1% -- -- Dry Mouth 1% 0% 2% <1% Vomiting -- -- 1% <1% Nervous System Dizziness 2% 1% -- -- Insomnia 1% <1% 3% <1% Somnolence 2% <1% 3% <1% Nervousness -- -- 2% <1% Tremor -- -- 1% 0% Skin Sweating -- -- 2% <1% 1 Two of the depression studies were flexible dose and one was fixed dose. Four of the GAD studies were fixed dose and one was flexible dose. 2 In U.S. placebo-controlled trials for depression, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 192], % Placebo [n = 202]: hypertension (1%, <1%); diarrhea (1%, 0%); paresthesia (1%, 0%); tremor (1%, 0%); abnormal vision, mostly blurred vision (1%, 0%); and abnormal, mostly delayed, ejaculation (1%, 0%). 3 In two short-term U.S. placebo-controlled trials for GAD, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 476], % Placebo [n = 201]): headache (4%, <1%); vasodilatation (1%, 0%); anorexia (2%, <1%); dizziness (4%, 1%); thinking abnormal (1%, 0%); and abnormal vision (1%, 0%). 4 In long-term placebo-controlled trials for GAD, the following was also a common event leading to discontinuation and was considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 535], % Placebo [n = 257]): decreased libido (1%, 0%). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 21 16 Mar 01 Adverse Events Occurring at an Incidence of 2% or More Among Effexor XR-Treated Patients Tables 3 and 4 enumerate the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of depression (up to 12 weeks; dose range of 75 to 225 mg/day) and of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR where the incidence in patients treated with Effexor XR was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART- based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Commonly Observed Adverse Events from Tables 3 and 4: Depression Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the depression indication (Table 3): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning. Generalized Anxiety Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 4): Abnormalities of sexual function (abnormal ejaculation and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 22 16 Mar 01 impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 23 16 Mar 01 TABLE 3 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Depressed Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n=357) Placebo (n=285) Body as a Whole Asthenia 8% 7% Cardiovascular System Vasodilatation3 Hypertension 4% 4% 2% 1% Digestive System Nausea Constipation Anorexia Vomiting Flatulence 31% 8% 8% 4% 4% 12% 5% 4% 2% 3% Metabolic/Nutritional Weight Loss 3% 0% Nervous System Dizziness Somnolence Insomnia Dry Mouth Nervousness Abnormal Dreams4 Tremor Depression Paresthesia Libido Decreased Agitation 20% 17% 17% 12% 10% 7% 5% 3% 3% 3% 3% 9% 8% 11% 6% 5% 2% 2% <1% 1% <1% 1% Respiratory System Pharyngitis Yawn 7% 3% 6% 0% Skin Sweating 14% 3% Special Senses Abnormal Vision5 4% <1% Urogenital System Abnormal Ejaculation (male)6,7 Impotence7 Anorgasmia (female)8,9 16% 4% 3% <1% <1% <1% 1. Incidence, rounded to the nearest %, for events reported by at least 2% of patients treated with Effexor XR, except the following events which had an incidence equal to or less than placebo: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis, and sinusitis. 2 <1% indicates an incidence greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5 Mostly “blurred vision” and “difficulty focusing eyes.” 6 Mostly “delayed ejaculation.” 7 Incidence is based on the number of male patients. 8 Mostly “delayed orgasm” or “anorgasmia.” 9 Incidence is based on the number of female patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 24 16 Mar 01 TABLE 4 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in GAD Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n=1381) Placebo (n=555) Body as a Whole Asthenia 12% 8% Cardiovascular System Vasodilatation3 4% 2% Digestive System Nausea 35% 12% Constipation 10% 4% Anorexia 8% 2% Vomiting 5% 3% Nervous System Dizziness 16% 11% Dry Mouth 16% 6% Insomnia 15% 10% Somnolence 14% 8% Nervousness 6% 4% Libido Decreased 4% 2% Tremor 4% <1% Abnormal Dreams4 3% 2% Hypertonia 3% 2% Paresthesia 2% 1% Respiratory System Yawn 3% <1% Skin Sweating 10% 3% Special Senses Abnormal Vision5 5% <1% Urogenital System Abnormal Ejaculation6,7 11% <1% Impotence7 5% <1% Orgasmic Dysfunction (female) 8,9 2% 0% 1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, pain, palpitation, pharyngitis, rhinitis, tinnitus, and urinary frequency. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5. Mostly “blurred vision” and “difficulty focusing eyes.” 6 Includes “delayed ejaculation” and “ 7 Percentage based on the number of males (Effexor XR = 525, placebo = 220). 8 Includes “delayed orgasm,” ”abnormal orgasm,” and “ 9 Percentage based on the number of females (Effexor XR = 856, placebo = 335). Vital Sign Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 25 16 Mar 01 premarketing placebo-controlled depression trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. (See the “Sustained Hypertension” section of “WARNINGS” for effects on blood pressure) Laboratory Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled depression trials was associated with a mean final on-therapy increases in serum cholesterol concentration of approximately 1.5 mg/dL. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively. These changes are of unknown clinical significance. ECG Changes (See the “Use in Patients with Concomitant Illnesses” PRECAUTIONS”). Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in phase 3 depression studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were administered to 1381 patients in phase 3 GAD studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in phase 2-3 depression studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 26 16 Mar 01 proportion of the 5079 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Tables 3 and 4 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system - Frequent: migraine, postural hypotension, tachycardia; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system - Frequent: eructation, increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system - Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 27 16 Mar 01 Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT increased, SGPT increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system - Frequent: arthralgia; Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, rheumatoid arthritis, tendon rupture. Nervous system - Frequent: amnesia, confusion, depersonalization, emotional lability, hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: apathy, ataxia, circumoral paresthesia, CNS stimulation, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor, twitching; Rare: akathisia, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, libido increased, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larnyx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages - Frequent: rash, pruritus; Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythremia nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 28 16 Mar 01 subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system - Frequent: dysuria, metrorrhagia, prostatic disorder (prostatitis and enlarged prostrate),* urination impaired, vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, hematuria, leukorrhea,* menorrhagia,* nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, breast discharge, breast engorgement, balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,* prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm.* *Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of Effexor (the immediate release form of venlafaxine) that have been received since market introduction and that may have no causal relationship with the use of Effexor include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities (such as atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia), epidermal necrosis/Stevens- Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including tardive dyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), pancreatitis, panic, prolactin increased, renal failure, serotonin syndrome, shock-like electrical sensations (in some cases, subsequent to the discontinuation of Effexor or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 29 16 Mar 01 DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (See “DOSAGE AND ADMINISTRATION”). While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in depression trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 30 16 Mar 01 were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week. Among the patients included in the premarketing evaluation with Effexor, there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 µg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), seizures, vertigo, and death have been reported. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 31 16 Mar 01 In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). DOSAGE AND ADMINISTRATION Effexor XR should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water. Initial Treatment Depression For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140-180 mg/day (see “Clinical Trials” under “CLINICAL PHARMACOLOGY”). It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (the immediate release form of venlafaxine), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited. Generalized Anxiety Disorder For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 32 16 Mar 01 patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. Switching Patients from Effexor Tablets Depressed patients who are currently being treated at a therapeutic dose with Effexor may be switched to Effexor XR at the nearest equivalent dose (mg/day), e.g., 37.5 mg venlafaxine two- times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary. Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared with normal subjects (see “CLINICAL PHARMACOLOGY”), it is recommended that the starting dose be reduced by 50% in patients with moderate hepatic impairment. Because there was much individual variability in clearance between patients with cirrhosis, individualization of dosage may be desirable in some patients. Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10-70 mL/min) compared with normal subjects (see “CLINICAL PHARMACOLOGY”), it is recommended that the total daily dose be reduced by 25%-50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50% and that the dose be withheld until the dialysis treatment is completed (4 hrs). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients. Elderly Patients No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of depression or generalized anxiety disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 33 16 Mar 01 Maintenance Treatment There is no body of evidence available from controlled trials to indicate how long patients with depression or generalized anxiety disorder should be treated with Effexor XR. It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for a period of up to 52 weeks on the same dose (100-200 mg/day, on a bid schedule) (see “Clinical Trials” under “CLINICAL PHARMACOLOGY”). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. In patients with Generalized Anxiety Disorder, Effexor XR has been shown to be effective in 6- month clinical trials. The need for continuing medication in patients with GAD who improve with Effexor XR treatment should be periodically reassessed. Discontinuing Effexor XR When discontinuing Effexor XR after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary. Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials of depression. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 34 16 Mar 01 nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. It is therefore recommended that the dose of Effexor XR be tapered gradually and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient. Discontinuation effects are well known to occur with antidepressants. Switching Patients To or From a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor XR. In addition, at least 7 days should be allowed after stopping Effexor XR before starting an MAOI (see “CONTRAINDICATIONS” and “WARNINGS”). HOW SUPPLIED Effexor® XR (venlafaxine hydrochloride) extended-release capsules are available as follows: 37.5 mg, grey cap/peach body with “ Effexor XR” on the cap and “37.5” on the body. NDC 0008-0837-01, bottle of 100 capsules. NDC 0008-0837-03, carton of 10 Redipak® blister strips of 10 capsules each. Store at controlled room temperature, 20°°C to 25°°C (68°°F to 77°°F). Bottles: Protect from light. Dispense in light-resistant container. Blisters: Protect from light. Use blister carton to protect contents from light. 75 mg, peach cap and body with “ Effexor XR” on the cap and “75” on the body. NDC 0008-0833-01, bottle of 100 capsules. NDC 0008-0833-03, carton of 10 Redipak® blister strips of 10 capsules each. Store at controlled room temperature, 20°°C to 25°°C (68°°F to 77°°F). 150 mg, dark orange cap and body with “ Effexor XR” on the cap and “150” on the body. NDC 0008-0836-01, bottle of 100 capsules. NDC 0008-0836-03, carton of 10 Redipak® blister strips of 10 capsules each. Store at controlled room temperature, 20°°C to 25°°C (68°°F to 77°°F). The appearance of these capsules is a trademark of Wyeth-Ayerst Laboratories. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR Relapse/Recurrence CONFIDENTIAL 35 16 Mar 01 Wyeth Laboratories Inc. A Wyeth-Ayerst Company Philadelphia, PA 19101 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:50.509697	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20151s17s18lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 17}
12,253	1 Effexor (venlafaxine hydrochloride) Tablets only This product’s label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Liver Disease In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic patients compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 WARNINGS Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on Effexor, or who have recently had Effexor therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with a monoamine oxidase inhibitor, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. Therefore, it is recommended that Effexor not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Effexor, at least 7 days should be allowed after stopping Effexor before starting an MAOI. Clinical Worsening and Suicide Risk Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms. Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuing Effexor, for a description of the risks of discontinuation of Effexor). It should be noted that Effexor is not approved for use in treating any indications in the pediatric population. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor is not approved for use in treating bipolar depression. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. PRECAUTIONS General Discontinuation of Treatment with Effexor Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock- like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Patients should be monitored for these symptoms when discontinuing treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short-term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety 6% 3% Nervousness 13% 6% Insomnia 18% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies. Changes in Appetite and Weight Treatment-emergent anorexia was more commonly reported for venlafaxine-treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. A dose-dependent weight loss was often noted in patients treated with venlafaxine for several weeks. Significant weight loss, especially in underweight depressed patients, may be an undesirable result of venlafaxine treatment. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression trials). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor and weight loss agents is not recommended. Effexor is not indicated for weight loss alone or in combination with other products. Activation of Mania/Hypomania During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Hyponatremia Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. This should be taken into consideration in patients who are, for example, volume-depleted, elderly, or taking diuretics. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow angle glaucoma should be monitored. Seizures During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Abnormal Bleeding There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor-treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. Information for Patients Physicians are advised to discuss the following issues with patients for whom they prescribe Effexor: Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient’s physician, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations, since there is a potential for interactions. Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Based on the mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, serotonin reuptake inhibitors (SRIs), or lithium. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis. Pregnancy Teratogenic Effects—Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Non-teratogenic Effects Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Usage in Children Safety and effectiveness in individuals below 18 years of age have not been established. (See WARNINGS-Clinical Worsening and Suicide Risk). Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: CNS Venlafaxine Placebo Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% — Nervousness 2% — Dry mouth 2% — Anxiety 2% 1% Gastrointestinal Nausea 6% 1% Urogenital Abnormal ejaculation* 3% — Other Headache 3% 1% Asthenia 2% — Sweating 2% — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor(incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. TABLE 1 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Body as a Whole Headache 25% 24% Asthenia 12% 6% Infection 6% 5% Chills 3% — Chest pain 2% 1% Trauma 2% 1% Cardiovascular Vasodilatation 4% 3% Increased blood pressure/hypertension 2% — Tachycardia 2% — Postural hypotension 1% — Dermatological Sweating 12% 3% Rash 3% 2% Pruritus 1% — Gastrointestinal Nausea 37% 11% Constipation 15% 7% Anorexia 11% 2% Diarrhea 8% 7% Vomiting 6% 2% Dyspepsia 5% 4% Flatulence 3% 2% Metabolic Weight loss 1% — This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Nervous System Somnolence 23% 9% Dry mouth 22% 11% Dizziness 19% 7% Insomnia 18% 10% Nervousness 13% 6% Anxiety 6% 3% Tremor 5% 1% Abnormal dreams 4% 3% Hypertonia 3% 2% Paresthesia 3% 2% Libido decreased 2% — Agitation 2% — Confusion 2% 1% Thinking abnormal 2% 1% Depersonalization 1% — Depression 1% — Urinary retention 1% — Twitching 1% — Respiration Yawn 3% — Special Senses Blurred vision 6% 2% Taste perversion 2% — Tinnitus 2% — Mydriasis 2% — Urogenital System Abnormal ejaculation/ orgasm 12%2 —2 Impotence 6%2 —2 Urinary frequency 3% 2% Urination impaired 2% — Orgasm disturbance 2%3 —3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 TABLE 2 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo 75 225 375 (n=92) (n=89) (n=89) (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% Cardiovascular System Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% (Number of men) (n=63) (n=52) (n=48) (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry mouth). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see WARNINGS). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment for Generalized Anxiety Disorder, multiple doses of Effexor XR were administered to 476 patients in Phase 3 studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 4174 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 1 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole—Frequent: chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt; Rare: appendicitis, bacteremia, carcinoma, cellulitis, withdrawal syndrome. Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mitral valve disorder, mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, oral moniliasis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, glycosuria, hypercholesteremia, hyperglycemia, hyperuricemia, hypoglycemia, hypokalemia, SGOT increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, dehydration, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperlipemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, SGPT increased, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: emotional lability, trismus, vertigo; Infrequent: apathy, ataxia, circumoral paresthesia, CNS stimulation, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, paranoid reaction, psychosis, seizure, abnormal speech, stupor; Rare: akathisia, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain-Barre Syndrome, hypokinesia, neuritis, nystagmus, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, exophthalmos, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia, prostatitis, vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, female lactation, leukorrhea, menorrhagia, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, prolonged erection, gynecomastia (male), hypomenorrhea, kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause, pyelonephritis, oliguria, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm.* * Based on the number of men and women as appropriate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, pulmonary eosinophilia, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (eg, development of tolerance, incrementation of dose, drug-seeking behavior). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 OVERDOSAGE Human Experience There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 µg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), rhabdomyolysis, seizures, vertigo, and death have been reported. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor in the third trimester. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% and the dose be withheld until the dialysis treatment is completed (4 hrs) in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Maintenance Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Discontinuing Effexor (venlafaxine hydrochloride) Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see CONTRAINDICATIONS and WARNINGS). HOW SUPPLIED Effexor (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “ ” on one side and “701” on scored reverse side. NDC 0008-0701-01, bottle of 100 tablets. NDC 0008-0701-02, carton of 10 Redipakblister strips of 10 tablets each. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “ ”on one side and “781” on scored reverse side. NDC 0008-0781-01, bottle of 100 tablets. NDC 0008-0781-02, carton of 10 Redipakblister strips of 10 tablets each. 50 mg, peach, shield-shaped tablet with “50” and a “ ” on one side and “703” on scored reverse side. NDC 0008-0703-01, bottle of 100 tablets. NDC 0008-0703-02, carton of 10 Redipakblister strips of 10 tablets each. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 75 mg, peach, shield-shaped tablet with “75” and a “ ” on one side and “704” on scored reverse side. NDC 0008-0704-01, bottle of 100 tablets. NDC 0008-0704-02, carton of 10 Redipakblister strips of 10 tablets each. 100 mg, peach, shield-shaped tablet with “100” and a “ ” on one side and “705” on scored reverse side. NDC 0008-0705-01, bottle of 100 tablets. NDC 0008-0705-02, carton of 10 Redipakblister strips of 10 tablets each. The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20º to 25ºC (68º to 77ºF) in a dry place. Dispense in a well-closed container as defined in the USP. Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 W10402C007 ET01 Rev 04/04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Effexor XR (venlafaxine hydrochloride) Extended-Release Capsules only This product’s label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. DESCRIPTION Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1- (4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]- p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 hydrochloride. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Effexor XR is formulated as an extended-release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively). Absorption Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for immediate release venlafaxine tablets (Cmax’s for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax’s were 2 hours for venlafaxine and 3 hours for ODV). When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Metabolism and Excretion Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion. Special Populations Age and Gender: A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Extensive/Poor Metabolizers: Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups. Liver Disease: In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic patients compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). Renal Disease: In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). Clinical Trials Major Depressive Disorder The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder. A 12-week study utilizing Effexor XR doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Effexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, Effexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score. A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing Effexor (the immediate release form of venlafaxine) in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of Effexor over placebo. The mean dose in completers was 350 mg/day. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. In one longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10, and (3) no single CGI Severity of Illness item score ≥4(moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. Generalized Anxiety Disorder The efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month, placebo-controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in outpatients meeting DSM-IV criteria for GAD. One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose. A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg/day dose range utilized in these two studies. Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and the other evaluating Effexor XR doses of 75 to 225 mg/day, showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. Social Anxiety Disorder (Social Phobia) The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in two double-blind, parallel group, 12-week, multicenter, placebo-controlled, flexible-dose studies in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75 to 225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these two trials, Effexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 INDICATIONS AND USAGE Major Depressive Disorder Effexor XR (venlafaxine hydrochloride) extended-release capsules is indicated for the treatment of major depressive disorder. The efficacy of Effexor XR in the treatment of major depressive disorder was established in 8- and 12-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The efficacy of Effexor (the immediate release form of venlafaxine) in the treatment of major depressive disorder in inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see Clinical Trials). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied. The efficacy of Effexor XR in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see Clinical Trials). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Generalized Anxiety Disorder Effexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in outpatients diagnosed with GAD according to DSM-IV criteria (see Clinical Trials). Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Social Anxiety Disorder Effexor XR is indicated for the treatment of Social Anxiety Disorder, also known as Social Phobia, as defined in DSM-IV (300.23). Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. The efficacy of Effexor XR in the treatment of Social Anxiety Disorder was established in two 12-week placebo-controlled trials in adult outpatients with Social Anxiety Disorder (DSM-IV). Effexor XR has not been studied in children or adolescents with Social Anxiety Disorder (see Clinical Trials). The effectiveness of Effexor XR in the long-term treatment of Social Anxiety Disorder, ie, for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 WARNINGS Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it is recommended that Effexor XR (venlafaxine hydrochloride) extended-release capsules not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI. Clinical Worsening and Suicide Risk Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms. Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuing Effexor XR, for a description of the risks of discontinuation of Effexor XR). It should be noted that Effexor XR is not approved for use in treating any indications in the pediatric population. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. Among patients treated with 75 to 375 mg/day of Effexor XR in premarketing studies in patients with major depressive disorder, 3% (19/705) experienced sustained hypertension [defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits]. Among patients treated with 37.5 to 225 mg/day of Effexor XR in premarketing GAD studies, 0.5% (5/1011) experienced sustained hypertension. Among patients treated with 75 to 225 mg/day of Effexor XR in premarketing Social Anxiety Disorder studies, 1.4% (4/277) experienced sustained hypertension. Experience with the immediate-release venlafaxine showed that sustained hypertension was dose-related, increasing from 3% to 7% at 100 to 300 mg/day to 13% at doses above 300 mg/day. An insufficient number This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. In placebo-controlled premarketing studies in patients with major depressive disorder with Effexor XR 75 to 225 mg/day, a final on-drug mean increase in supine diastolic blood pressure (SDBP) of 1.2 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.2 mm Hg for placebo-treated patients. In placebo-controlled premarketing GAD studies with Effexor XR 37.5 to 225 mg/day, up to 8 weeks or up to 6 months, a final on-drug mean increase in SDBP of 0.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.9 and 0.8 mm Hg, respectively, for placebo-treated patients. In placebo-controlled premarketing Social Anxiety Disorder studies with Effexor XR 75 to 225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 1.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 1.3 mm Hg for placebo-treated patients. In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 12 weeks, 0.4% (1/277) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In this patient, the blood pressure increase was modest (13 mm Hg, SDBP). Sustained increases of SDBP could have adverse consequences. Therefore, it is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. PRECAUTIONS General Discontinuation of Treatment with Effexor XR Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 During marketing of Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Insomnia and Nervousness Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, GAD, and Social Anxiety Disorder studies, as shown in Table 1. Table 1 Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder, GAD, and Social Anxiety Disorder Trials Major Depressive Disorder GAD Social Anxiety Disorder Symptom Effexor XR n = 357 Placebo n = 285 Effexor XR n = 1381 Placebo n = 555 Effexor XR n = 277 Placebo n = 274 Insomnia 17% 11% 15% 10% 23% 7% Nervousness 10% 5% 6% 4% 11% 3% Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in major depressive disorder studies. In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with Effexor XR up to 6 months. In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 3% and 0%, respectively, of the patients treated with Effexor XR up to 12 weeks. Changes in Appetite and Weight Treatment-emergent anorexia was more commonly reported for Effexor XR treated (8%) than placebo treated patients (4%) in the pool of short-term studies in major depressive disorder. Significant weight loss, especially in underweight depressed patients, may be an undesirable effect of Effexor XR treatment. A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in placebo-controlled major depressive This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 disorder trials. Discontinuation rates for anorexia and weight loss associated with Effexor XR were low (1.0% and 0.1%, respectively, of Effexor XR treated patients in major depressive disorder studies). In the pool of GAD studies, treatment emergent anorexia was reported in 8% and 2% of patients receiving Effexor XR and placebo up to 8 weeks, respectively. A loss of 7% or more of body weight occurred in 3% of the Effexor XR-treated and 1% of the placebo-treated patients up to 6 months in these trials. Discontinuation rates for anorexia and weight loss were low for patients receiving Effexor XR up to 8 weeks (0.9% and 0.3%, respectively). In the pool of Social Anxiety Disorder studies, treatment emergent anorexia was reported in 20% and 2% of patients receiving Effexor XR and placebo up to 12 weeks, respectively. A loss of 7% or more of body weight occurred in 3% of the Effexor XR-treated and 0.4% of the placebo-treated patients up to 12 weeks in these trials. Discontinuation rates for anorexia and weight loss were low for patients receiving Effexor XR up to 12 weeks (0.4% and 0.0%, respectively). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products. Activation of Mania/Hypomania During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of Effexor XR-treated patients and 0.0% placebo patients. In premarketing GAD studies, 0.0% of Effexor XR-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing Social Anxiety Disorder studies, no Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with Effexor, mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with 0% of placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Effexor XR should be used cautiously in patients with a history of mania. Hyponatremia Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. This should be taken into consideration in patients who are, for example, volume-depleted, elderly, or taking diuretics. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma should be monitored. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Seizures During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies, or among 277 Effexor XR-treated patients in Social Anxiety Disorder studies. In all premarketing major depressive disorder trials with Effexor, seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures. Abnormal Bleeding There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS-Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Use in Patients With Concomitant Illness Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor XR to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received Effexor XR and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder, for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD, and for 195 patients who received Effexor XR and 228 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. The mean change from baseline in QTc for Effexor XR-treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 2.8 msec for Effexor XR and decrease of 2.0 msec for placebo). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for Effexor XR and no change for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. Evaluation of the electrocardiograms for 769 patients who received immediate release Effexor in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor XR, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients. Information for Patients Physicians are advised to discuss the following issues with patients for whom they prescribe Effexor XR (venlafaxine hydrochloride) extended-release capsules: Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient’s physician, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations, since there is a potential for interactions. Alcohol Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Proteins Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion under CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce simultaneous inhibition of these two enzyme systems. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC’s increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Based on the mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, serotonin reuptake inhibitors (SRIs), or lithium. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenesis Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose on a mg/m2 basis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Pregnancy Teratogenic Effects - Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. (See WARNINGS-Clinical Worsening and Suicide Risk). Geriatric Use Approximately 4% (14/357), 6% (77/1381), and 2% (6/277) of Effexor XR-treated patients in placebo-controlled premarketing major depressive disorder, GAD, and Social Anxiety Disorder trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated patients in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS The information included in the Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR, and on data up to 12 weeks from a pool of two controlled clinical trials in Social Anxiety Disorder. Information on additional adverse events associated with Effexor XR in the entire development program for the formulation and with Effexor (the immediate release formulation of venlafaxine) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR subsection (see also WARNINGS and PRECAUTIONS). Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR Adverse Events Associated with Discontinuation of Treatment Approximately 11% of the 357 patients who received EffexorXR (venlafaxine hydrochloride) extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 17% of the 277 patients who received Effexor XR capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 274 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for either indication) are shown in Table 2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 Table 2 Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials1 Percentage of Patients Discontinuing Due to Adverse Event Adverse Event Major Depressive Disorder Indication2 GAD Indication3,4 Social Anxiety Disorder Indication Effexor XR n = 357 Placebo n = 285 Effexor XR n = 1381 Placebo n = 555 Effexor XR n = 277 Placebo n = 274 Body as a Whole Asthenia -- -- 3% <1% 1% <1% Headache -- -- -- -- 2% <1% Digestive System Nausea 4% <1% 8% <1% 4% 0% Anorexia 1% <1% -- -- -- -- Dry Mouth 1% 0% 2% <1% -- -- Vomiting -- -- 1% <1% -- -- Nervous System Dizziness 2% 1% -- -- 2% 0% Insomnia 1% <1% 3% <1% 3% <1% Somnolence 2% <1% 3% <1% 2% <1% Nervousness -- -- 2% <1% -- -- Tremor -- -- 1% 0% -- -- Anxiety -- -- -- -- 1% <1% Skin Sweating -- -- 2% <1% 1% 0% Urogenital System Impotence5 -- -- -- -- 3% 0% 1 Two of the major depressive disorder studies were flexible dose and one was fixed dose. Four of the GAD studies were fixed dose and one was flexible dose. Both of the Social Anxiety Disorder studies were flexible dose. 2 In U.S. placebo-controlled trials for major depressive disorder, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 192], % Placebo [n = 202]): hypertension (1%, <1%); diarrhea (1%, 0%); paresthesia (1%, 0%); tremor (1%, 0%); abnormal vision, mostly blurred vision (1%, 0%); and abnormal, mostly delayed, ejaculation (1%, 0%). 3 In two short-term U.S. placebo-controlled trials for GAD, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 476]), % Placebo [n = 201]: headache (4%, <1%); vasodilatation (1%, 0%); anorexia (2%, <1%); dizziness (4%, 1%); thinking abnormal (1%, 0%); and abnormal vision (1%, 0%). 4 In long-term placebo-controlled trials for GAD, the following was also a common event leading to discontinuation and was considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 535], % Placebo [n = 257]): decreased libido (1%, 0%). 5 Incidence is based on the number of men (Effexor XR = 158, placebo = 153). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Adverse Events Occurring at an Incidence of 2% or More Among Effexor XR-Treated Patients Tables 3, 4, and 5 enumerate the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day), of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), and of Social Anxiety Disorder (up to 12 weeks; dose range of 75 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR (venlafaxine hydrochloride) where the incidence in patients treated with Effexor XR was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Commonly Observed Adverse Events from Tables 3, 4, and 5: Major Depressive Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder (Table 3): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning. Generalized Anxiety Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 4): Abnormalities of sexual function (abnormal ejaculation and impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Social Anxiety Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for the 2 placebo-controlled trials for the Social Anxiety Disorder indication (Table 5): Asthenia, gastrointestinal complaints (anorexia, dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness, somnolence, dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmic dysfunction, impotence), yawn, sweating, and abnormal vision. Table 3 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Patients with Major Depressive Disorder1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 357) Placebo (n = 285) Body as a Whole Asthenia 8% 7% Cardiovascular System Vasodilatation3 4% 2% Hypertension 4% 1% Digestive System Nausea 31% 12% Constipation 8% 5% Anorexia 8% 4% Vomiting 4% 2% Flatulence 4% 3% Metabolic/Nutritional Weight Loss 3% 0% Nervous System Dizziness 20% 9% Somnolence 17% 8% Insomnia 17% 11% Dry Mouth 12% 6% Nervousness 10% 5% Abnormal Dreams4 7% 2% Tremor 5% 2% Depression 3% <1% Paresthesia 3% 1% Libido Decreased 3% <1% Agitation 3% 1% Respiratory System Pharyngitis 7% 6% Yawn 3% 0% Skin Sweating 14% 3% Special Senses Abnormal Vision5 4% <1% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 % Reporting Event Body System Preferred Term Effexor XR (n = 357) Placebo (n = 285) Urogenital System Abnormal Ejaculation 16% <1% (male)6,7 Impotence7 4% <1% Anorgasmia (female)8,9 3% <1% 1 Incidence, rounded to the nearest %, for events reported by at least 2% of patients treated with Effexor XR, except the following events which had an incidence equal to or less than placebo: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis, and sinusitis. 2 <1% indicates an incidence greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5 Mostly “blurred vision” and “difficulty focusing eyes.” 6 Mostly “delayed ejaculation.” 7 Incidence is based on the number of male patients. 8 Mostly “delayed orgasm” or “anorgasmia.” 9 Incidence is based on the number of female patients. Table 4 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in GAD Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 1381) Placebo (n = 555) Body as a Whole Asthenia 12% 8% Cardiovascular System Vasodilatation3 4% 2% Digestive System Nausea 35% 12% Constipation 10% 4% Anorexia 8% 2% Vomiting 5% 3% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 % Reporting Event Body System Preferred Term Effexor XR (n = 1381) Placebo (n = 555) Nervous System Dizziness 16% 11% Dry Mouth 16% 6% Insomnia 15% 10% Somnolence 14% 8% Nervousness 6% 4% Libido Decreased 4% 2% Tremor 4% <1% Abnormal Dreams4 3% 2% Hypertonia 3% 2% Paresthesia 2% 1% Respiratory System Yawn 3% <1% Skin Sweating 10% 3% Special Senses Abnormal Vision5 5% <1% Urogenital System Abnormal Ejaculation6,7 11% <1% Impotence7 5% <1% Orgasmic Dysfunction (female)8,9 2% 0% 1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, pain, palpitation, pharyngitis, rhinitis, tinnitus, and urinary frequency. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5 Mostly “blurred vision” and “difficulty focusing eyes.” 6 Includes “delayed ejaculation” and “anorgasmia.” 7 Percentage based on the number of males (Effexor XR = 525, placebo = 220). 8 Includes “delayed orgasm,” “abnormal orgasm,” and “anorgasmia.” 9 Percentage based on the number of females (Effexor XR = 856, placebo = 335). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Table 5 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Social Anxiety Disorder Patients1,2 % Reporting Event Body System Effexor XR Placebo Preferred Term (n = 277) (n = 274) Body as a Whole Headache 34% 33% Asthenia 17% 8% Flu Syndrome 6% 5% Accidental Injury 5% 3% Abdominal Pain 4% 3% Cardiovascular System Hypertension 5% 4% Vasodilatation3 3% 1% Palpitation 3% 1% Digestive System Nausea 29% 9% Anorexia4 20% 1% Constipation 8% 4% Diarrhea 6% 5% Vomiting 3% 2% Eructation 2% 0% Metabolic/Nutritional Weight Loss 4% 0% Nervous System Insomnia 23% 7% Dry Mouth 17% 4% Dizziness 16% 8% Somnolence 16% 8% Nervousness 11% 3% Libido Decreased 9% <1% Anxiety 5% 3% Agitation 4% 1% Tremor 4% <1% Abnormal Dreams5 4% <1% Paresthesia 3% <1% Twitching 2% 0% Respiratory System Yawn 5% <1% Sinusitis 2% 1% Skin Sweating 13% 2% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 % Reporting Event Body System Effexor XR Placebo Preferred Term (n = 277) (n = 274) Special Senses Abnormal Vision6 6% 3% Urogenital System Abnormal Ejaculation7,8 16% 1% Impotence8 10% 1% Orgasmic Dysfunction9,10 8% 0% 1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: back pain, depression, dysmenorrhea, dyspepsia, infection, myalgia, pain, pharyngitis, rash, rhinitis, and upper respiratory infection. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “decreased appetite” and “loss of appetite.” 5 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 6 Mostly “blurred vision.” 7 Includes “delayed ejaculation” and “anorgasmia.” 8 Percentage based on the number of males (Effexor XR = 158, placebo = 153). 9 Includes “abnormal orgasm” and “anorgasmia.” 10 Percentage based on the number of females (Effexor XR = 119, placebo = 121). Vital Sign Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 4 beats per minute, compared with an increase of 1 beat per minute for placebo. (See the Sustained Hypertension section of WARNINGS for effects on blood pressure.) In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. Laboratory Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 11.4 mg/dL compared with a mean final decrease of 2.2 mg/dL for placebo. Patients treated with Effexor tablets (the immediate-release form of venlafaxine) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS). Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Tables 3, 4, and 5 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system - Frequent: migraine, postural hypotension, tachycardia; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system - Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT increased, SGPT increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system - Frequent: arthralgia; Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system - Frequent: metrorrhagia,* prostatic disorder (prostatitis and enlarged prostate),* urination impaired, vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea,* menorrhagia,* nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, breast discharge, breast engorgement, balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,* prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm,* vaginal dryness.* *Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, pulmonary eosinophilia, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (eg, development of tolerance, incrementation of dose, drug-seeking behavior). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 OVERDOSAGE Human Experience Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week. There were no reports of acute overdose with Effexor XR in Social Anxiety Disorder trials. Among the patients included in the premarketing evaluation with Effexor, there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 µg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), rhabdomyolysis, seizures, vertigo, and death have been reported. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference(PDR). DOSAGE AND ADMINISTRATION Effexor XR should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water, or it may be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets. Initial Treatment Major Depressive Disorder For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (the immediate release form of venlafaxine), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited. (See PRECAUTIONS-General-Use in Patients with Concomitant Illness.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 Generalized Anxiety Disorder For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) Social Anxiety Disorder (Social Phobia) For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Social Anxiety Disorder, the initial dose of Effexor XR was 75 mg/day and the maximum dose was 225 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in patients with Social Anxiety Disorder was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS). Switching Patients from Effexor Tablets Depressed patients who are currently being treated at a therapeutic dose with Effexor may be switched to Effexor XR at the nearest equivalent dose (mg/day), eg, 37.5 mg venlafaxine two-times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor XR in the third trimester. Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the starting dose be reduced by 50% in patients with moderate hepatic impairment. Because there was much individual variability in clearance between patients with cirrhosis, individualization of dosage may be desirable in some patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50% and that the dose be withheld until the dialysis treatment is completed (4 hrs). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients. Elderly Patients No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, Generalized Anxiety Disorder, or Social Anxiety Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment There is no body of evidence available from controlled trials to indicate how long patients with major depressive disorder, Generalized Anxiety Disorder, or Social Anxiety Disorder should be treated with Effexor XR. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. In patients with Generalized Anxiety Disorder, Effexor XR has been shown to be effective in 6-month clinical trials. The need for continuing medication in patients with GAD who improve with Effexor XR treatment should be periodically reassessed. In patients with Social Anxiety Disorder, there are no efficacy data beyond 12 weeks of treatment with Effexor XR. The need for continuing medication in patients with Social Anxiety Disorder who improve with Effexor XR treatment should be periodically reassessed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 36 Discontinuing Effexor XR Symptoms associated with discontinuation of Effexor XR, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary. Switching Patients To or From a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor XR. In addition, at least 7 days should be allowed after stopping Effexor XR before starting an MAOI (see CONTRAINDICATIONS and WARNINGS). HOW SUPPLIED EffexorXR (venlafaxine hydrochloride) extended-release capsules are available as follows: 37.5 mg, grey cap/peach body with and “Effexor XR” on the cap and “37.5” on the body. NDC 0008-0837-01, bottle of 100 capsules. NDC 0008-0837-03, carton of 10 Redipakblister strips of 10 capsules each. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). 75 mg, peach cap and body with and “Effexor XR” on the cap and “75” on the body. NDC 0008-0833-01, bottle of 100 capsules. NDC 0008-0833-03, carton of 10 Redipakblister strips of 10 capsules each. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). 150 mg, dark orange cap and body with and “Effexor XR” on the cap and “150” on the body. NDC 0008-0836-01, bottle of 100 capsules. NDC 0008-0836-03, carton of 10 Redipakblister strips of 10 capsules each. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). The appearance of these capsules is a trademark of Wyeth Pharmaceuticals. Wyeth Pharmaceuticals Inc. W10404C009 Philadelphia, PA 19101 ET01 Rev 04/04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:50.872519	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20151slr028,030,032,20699slr041,048,052_effexor_lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 32}
12,252	1 Effexor (venlafaxine hydrochloride) Tablets only This product’s label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Liver Disease In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic patients compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 WARNINGS Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on Effexor, or who have recently had Effexor therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with a monoamine oxidase inhibitor, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. Therefore, it is recommended that Effexor not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Effexor, at least 7 days should be allowed after stopping Effexor before starting an MAOI. Clinical Worsening and Suicide Risk Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms. Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuing Effexor, for a description of the risks of discontinuation of Effexor). It should be noted that Effexor is not approved for use in treating any indications in the pediatric population. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor is not approved for use in treating bipolar depression. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. PRECAUTIONS General Discontinuation of Treatment with Effexor Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock- like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Patients should be monitored for these symptoms when discontinuing treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short-term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety 6% 3% Nervousness 13% 6% Insomnia 18% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies. Changes in Appetite and Weight Treatment-emergent anorexia was more commonly reported for venlafaxine-treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. A dose-dependent weight loss was often noted in patients treated with venlafaxine for several weeks. Significant weight loss, especially in underweight depressed patients, may be an undesirable result of venlafaxine treatment. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression trials). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor and weight loss agents is not recommended. Effexor is not indicated for weight loss alone or in combination with other products. Activation of Mania/Hypomania During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Hyponatremia Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. This should be taken into consideration in patients who are, for example, volume-depleted, elderly, or taking diuretics. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow angle glaucoma should be monitored. Seizures During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Abnormal Bleeding There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor-treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. Information for Patients Physicians are advised to discuss the following issues with patients for whom they prescribe Effexor: Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient’s physician, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations, since there is a potential for interactions. Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Based on the mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, serotonin reuptake inhibitors (SRIs), or lithium. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis. Pregnancy Teratogenic Effects—Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Non-teratogenic Effects Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Usage in Children Safety and effectiveness in individuals below 18 years of age have not been established. (See WARNINGS-Clinical Worsening and Suicide Risk). Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: CNS Venlafaxine Placebo Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% — Nervousness 2% — Dry mouth 2% — Anxiety 2% 1% Gastrointestinal Nausea 6% 1% Urogenital Abnormal ejaculation* 3% — Other Headache 3% 1% Asthenia 2% — Sweating 2% — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor(incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. TABLE 1 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Body as a Whole Headache 25% 24% Asthenia 12% 6% Infection 6% 5% Chills 3% — Chest pain 2% 1% Trauma 2% 1% Cardiovascular Vasodilatation 4% 3% Increased blood pressure/hypertension 2% — Tachycardia 2% — Postural hypotension 1% — Dermatological Sweating 12% 3% Rash 3% 2% Pruritus 1% — Gastrointestinal Nausea 37% 11% Constipation 15% 7% Anorexia 11% 2% Diarrhea 8% 7% Vomiting 6% 2% Dyspepsia 5% 4% Flatulence 3% 2% Metabolic Weight loss 1% — This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Nervous System Somnolence 23% 9% Dry mouth 22% 11% Dizziness 19% 7% Insomnia 18% 10% Nervousness 13% 6% Anxiety 6% 3% Tremor 5% 1% Abnormal dreams 4% 3% Hypertonia 3% 2% Paresthesia 3% 2% Libido decreased 2% — Agitation 2% — Confusion 2% 1% Thinking abnormal 2% 1% Depersonalization 1% — Depression 1% — Urinary retention 1% — Twitching 1% — Respiration Yawn 3% — Special Senses Blurred vision 6% 2% Taste perversion 2% — Tinnitus 2% — Mydriasis 2% — Urogenital System Abnormal ejaculation/ orgasm 12%2 —2 Impotence 6%2 —2 Urinary frequency 3% 2% Urination impaired 2% — Orgasm disturbance 2%3 —3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 TABLE 2 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo 75 225 375 (n=92) (n=89) (n=89) (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% Cardiovascular System Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% (Number of men) (n=63) (n=52) (n=48) (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry mouth). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see WARNINGS). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment for Generalized Anxiety Disorder, multiple doses of Effexor XR were administered to 476 patients in Phase 3 studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 4174 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 1 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole—Frequent: chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt; Rare: appendicitis, bacteremia, carcinoma, cellulitis, withdrawal syndrome. Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mitral valve disorder, mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, oral moniliasis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, glycosuria, hypercholesteremia, hyperglycemia, hyperuricemia, hypoglycemia, hypokalemia, SGOT increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, dehydration, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperlipemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, SGPT increased, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: emotional lability, trismus, vertigo; Infrequent: apathy, ataxia, circumoral paresthesia, CNS stimulation, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, paranoid reaction, psychosis, seizure, abnormal speech, stupor; Rare: akathisia, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain-Barre Syndrome, hypokinesia, neuritis, nystagmus, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, exophthalmos, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia, prostatitis, vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, female lactation, leukorrhea, menorrhagia, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, prolonged erection, gynecomastia (male), hypomenorrhea, kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause, pyelonephritis, oliguria, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm.* * Based on the number of men and women as appropriate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, pulmonary eosinophilia, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (eg, development of tolerance, incrementation of dose, drug-seeking behavior). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 OVERDOSAGE Human Experience There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 µg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), rhabdomyolysis, seizures, vertigo, and death have been reported. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor in the third trimester. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% and the dose be withheld until the dialysis treatment is completed (4 hrs) in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Maintenance Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Discontinuing Effexor (venlafaxine hydrochloride) Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see CONTRAINDICATIONS and WARNINGS). HOW SUPPLIED Effexor (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “ ” on one side and “701” on scored reverse side. NDC 0008-0701-01, bottle of 100 tablets. NDC 0008-0701-02, carton of 10 Redipakblister strips of 10 tablets each. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “ ”on one side and “781” on scored reverse side. NDC 0008-0781-01, bottle of 100 tablets. NDC 0008-0781-02, carton of 10 Redipakblister strips of 10 tablets each. 50 mg, peach, shield-shaped tablet with “50” and a “ ” on one side and “703” on scored reverse side. NDC 0008-0703-01, bottle of 100 tablets. NDC 0008-0703-02, carton of 10 Redipakblister strips of 10 tablets each. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 75 mg, peach, shield-shaped tablet with “75” and a “ ” on one side and “704” on scored reverse side. NDC 0008-0704-01, bottle of 100 tablets. NDC 0008-0704-02, carton of 10 Redipakblister strips of 10 tablets each. 100 mg, peach, shield-shaped tablet with “100” and a “ ” on one side and “705” on scored reverse side. NDC 0008-0705-01, bottle of 100 tablets. NDC 0008-0705-02, carton of 10 Redipakblister strips of 10 tablets each. The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20º to 25ºC (68º to 77ºF) in a dry place. Dispense in a well-closed container as defined in the USP. Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 W10402C007 ET01 Rev 04/04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Effexor XR (venlafaxine hydrochloride) Extended-Release Capsules only This product’s label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. DESCRIPTION Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1- (4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]- p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 hydrochloride. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Effexor XR is formulated as an extended-release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively). Absorption Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for immediate release venlafaxine tablets (Cmax’s for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax’s were 2 hours for venlafaxine and 3 hours for ODV). When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Metabolism and Excretion Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion. Special Populations Age and Gender: A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Extensive/Poor Metabolizers: Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups. Liver Disease: In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic patients compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). Renal Disease: In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). Clinical Trials Major Depressive Disorder The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder. A 12-week study utilizing Effexor XR doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Effexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, Effexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score. A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing Effexor (the immediate release form of venlafaxine) in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of Effexor over placebo. The mean dose in completers was 350 mg/day. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. In one longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10, and (3) no single CGI Severity of Illness item score ≥4(moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. Generalized Anxiety Disorder The efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month, placebo-controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in outpatients meeting DSM-IV criteria for GAD. One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose. A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg/day dose range utilized in these two studies. Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and the other evaluating Effexor XR doses of 75 to 225 mg/day, showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. Social Anxiety Disorder (Social Phobia) The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in two double-blind, parallel group, 12-week, multicenter, placebo-controlled, flexible-dose studies in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75 to 225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these two trials, Effexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 INDICATIONS AND USAGE Major Depressive Disorder Effexor XR (venlafaxine hydrochloride) extended-release capsules is indicated for the treatment of major depressive disorder. The efficacy of Effexor XR in the treatment of major depressive disorder was established in 8- and 12-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The efficacy of Effexor (the immediate release form of venlafaxine) in the treatment of major depressive disorder in inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see Clinical Trials). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied. The efficacy of Effexor XR in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see Clinical Trials). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Generalized Anxiety Disorder Effexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in outpatients diagnosed with GAD according to DSM-IV criteria (see Clinical Trials). Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Social Anxiety Disorder Effexor XR is indicated for the treatment of Social Anxiety Disorder, also known as Social Phobia, as defined in DSM-IV (300.23). Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. The efficacy of Effexor XR in the treatment of Social Anxiety Disorder was established in two 12-week placebo-controlled trials in adult outpatients with Social Anxiety Disorder (DSM-IV). Effexor XR has not been studied in children or adolescents with Social Anxiety Disorder (see Clinical Trials). The effectiveness of Effexor XR in the long-term treatment of Social Anxiety Disorder, ie, for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 WARNINGS Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it is recommended that Effexor XR (venlafaxine hydrochloride) extended-release capsules not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI. Clinical Worsening and Suicide Risk Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms. Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuing Effexor XR, for a description of the risks of discontinuation of Effexor XR). It should be noted that Effexor XR is not approved for use in treating any indications in the pediatric population. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. Among patients treated with 75 to 375 mg/day of Effexor XR in premarketing studies in patients with major depressive disorder, 3% (19/705) experienced sustained hypertension [defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits]. Among patients treated with 37.5 to 225 mg/day of Effexor XR in premarketing GAD studies, 0.5% (5/1011) experienced sustained hypertension. Among patients treated with 75 to 225 mg/day of Effexor XR in premarketing Social Anxiety Disorder studies, 1.4% (4/277) experienced sustained hypertension. Experience with the immediate-release venlafaxine showed that sustained hypertension was dose-related, increasing from 3% to 7% at 100 to 300 mg/day to 13% at doses above 300 mg/day. An insufficient number This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. In placebo-controlled premarketing studies in patients with major depressive disorder with Effexor XR 75 to 225 mg/day, a final on-drug mean increase in supine diastolic blood pressure (SDBP) of 1.2 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.2 mm Hg for placebo-treated patients. In placebo-controlled premarketing GAD studies with Effexor XR 37.5 to 225 mg/day, up to 8 weeks or up to 6 months, a final on-drug mean increase in SDBP of 0.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.9 and 0.8 mm Hg, respectively, for placebo-treated patients. In placebo-controlled premarketing Social Anxiety Disorder studies with Effexor XR 75 to 225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 1.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 1.3 mm Hg for placebo-treated patients. In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 12 weeks, 0.4% (1/277) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In this patient, the blood pressure increase was modest (13 mm Hg, SDBP). Sustained increases of SDBP could have adverse consequences. Therefore, it is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. PRECAUTIONS General Discontinuation of Treatment with Effexor XR Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 During marketing of Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Insomnia and Nervousness Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, GAD, and Social Anxiety Disorder studies, as shown in Table 1. Table 1 Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder, GAD, and Social Anxiety Disorder Trials Major Depressive Disorder GAD Social Anxiety Disorder Symptom Effexor XR n = 357 Placebo n = 285 Effexor XR n = 1381 Placebo n = 555 Effexor XR n = 277 Placebo n = 274 Insomnia 17% 11% 15% 10% 23% 7% Nervousness 10% 5% 6% 4% 11% 3% Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in major depressive disorder studies. In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with Effexor XR up to 6 months. In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 3% and 0%, respectively, of the patients treated with Effexor XR up to 12 weeks. Changes in Appetite and Weight Treatment-emergent anorexia was more commonly reported for Effexor XR treated (8%) than placebo treated patients (4%) in the pool of short-term studies in major depressive disorder. Significant weight loss, especially in underweight depressed patients, may be an undesirable effect of Effexor XR treatment. A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in placebo-controlled major depressive This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 disorder trials. Discontinuation rates for anorexia and weight loss associated with Effexor XR were low (1.0% and 0.1%, respectively, of Effexor XR treated patients in major depressive disorder studies). In the pool of GAD studies, treatment emergent anorexia was reported in 8% and 2% of patients receiving Effexor XR and placebo up to 8 weeks, respectively. A loss of 7% or more of body weight occurred in 3% of the Effexor XR-treated and 1% of the placebo-treated patients up to 6 months in these trials. Discontinuation rates for anorexia and weight loss were low for patients receiving Effexor XR up to 8 weeks (0.9% and 0.3%, respectively). In the pool of Social Anxiety Disorder studies, treatment emergent anorexia was reported in 20% and 2% of patients receiving Effexor XR and placebo up to 12 weeks, respectively. A loss of 7% or more of body weight occurred in 3% of the Effexor XR-treated and 0.4% of the placebo-treated patients up to 12 weeks in these trials. Discontinuation rates for anorexia and weight loss were low for patients receiving Effexor XR up to 12 weeks (0.4% and 0.0%, respectively). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products. Activation of Mania/Hypomania During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of Effexor XR-treated patients and 0.0% placebo patients. In premarketing GAD studies, 0.0% of Effexor XR-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing Social Anxiety Disorder studies, no Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with Effexor, mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with 0% of placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Effexor XR should be used cautiously in patients with a history of mania. Hyponatremia Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. This should be taken into consideration in patients who are, for example, volume-depleted, elderly, or taking diuretics. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma should be monitored. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Seizures During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies, or among 277 Effexor XR-treated patients in Social Anxiety Disorder studies. In all premarketing major depressive disorder trials with Effexor, seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures. Abnormal Bleeding There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS-Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Use in Patients With Concomitant Illness Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor XR to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received Effexor XR and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder, for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD, and for 195 patients who received Effexor XR and 228 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. The mean change from baseline in QTc for Effexor XR-treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 2.8 msec for Effexor XR and decrease of 2.0 msec for placebo). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for Effexor XR and no change for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. Evaluation of the electrocardiograms for 769 patients who received immediate release Effexor in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor XR, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients. Information for Patients Physicians are advised to discuss the following issues with patients for whom they prescribe Effexor XR (venlafaxine hydrochloride) extended-release capsules: Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient’s physician, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations, since there is a potential for interactions. Alcohol Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Proteins Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion under CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce simultaneous inhibition of these two enzyme systems. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC’s increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Based on the mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, serotonin reuptake inhibitors (SRIs), or lithium. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenesis Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose on a mg/m2 basis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Pregnancy Teratogenic Effects - Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. (See WARNINGS-Clinical Worsening and Suicide Risk). Geriatric Use Approximately 4% (14/357), 6% (77/1381), and 2% (6/277) of Effexor XR-treated patients in placebo-controlled premarketing major depressive disorder, GAD, and Social Anxiety Disorder trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated patients in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS The information included in the Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR, and on data up to 12 weeks from a pool of two controlled clinical trials in Social Anxiety Disorder. Information on additional adverse events associated with Effexor XR in the entire development program for the formulation and with Effexor (the immediate release formulation of venlafaxine) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR subsection (see also WARNINGS and PRECAUTIONS). Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR Adverse Events Associated with Discontinuation of Treatment Approximately 11% of the 357 patients who received EffexorXR (venlafaxine hydrochloride) extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 17% of the 277 patients who received Effexor XR capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 274 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for either indication) are shown in Table 2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 Table 2 Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials1 Percentage of Patients Discontinuing Due to Adverse Event Adverse Event Major Depressive Disorder Indication2 GAD Indication3,4 Social Anxiety Disorder Indication Effexor XR n = 357 Placebo n = 285 Effexor XR n = 1381 Placebo n = 555 Effexor XR n = 277 Placebo n = 274 Body as a Whole Asthenia -- -- 3% <1% 1% <1% Headache -- -- -- -- 2% <1% Digestive System Nausea 4% <1% 8% <1% 4% 0% Anorexia 1% <1% -- -- -- -- Dry Mouth 1% 0% 2% <1% -- -- Vomiting -- -- 1% <1% -- -- Nervous System Dizziness 2% 1% -- -- 2% 0% Insomnia 1% <1% 3% <1% 3% <1% Somnolence 2% <1% 3% <1% 2% <1% Nervousness -- -- 2% <1% -- -- Tremor -- -- 1% 0% -- -- Anxiety -- -- -- -- 1% <1% Skin Sweating -- -- 2% <1% 1% 0% Urogenital System Impotence5 -- -- -- -- 3% 0% 1 Two of the major depressive disorder studies were flexible dose and one was fixed dose. Four of the GAD studies were fixed dose and one was flexible dose. Both of the Social Anxiety Disorder studies were flexible dose. 2 In U.S. placebo-controlled trials for major depressive disorder, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 192], % Placebo [n = 202]): hypertension (1%, <1%); diarrhea (1%, 0%); paresthesia (1%, 0%); tremor (1%, 0%); abnormal vision, mostly blurred vision (1%, 0%); and abnormal, mostly delayed, ejaculation (1%, 0%). 3 In two short-term U.S. placebo-controlled trials for GAD, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 476]), % Placebo [n = 201]: headache (4%, <1%); vasodilatation (1%, 0%); anorexia (2%, <1%); dizziness (4%, 1%); thinking abnormal (1%, 0%); and abnormal vision (1%, 0%). 4 In long-term placebo-controlled trials for GAD, the following was also a common event leading to discontinuation and was considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 535], % Placebo [n = 257]): decreased libido (1%, 0%). 5 Incidence is based on the number of men (Effexor XR = 158, placebo = 153). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 Adverse Events Occurring at an Incidence of 2% or More Among Effexor XR-Treated Patients Tables 3, 4, and 5 enumerate the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day), of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), and of Social Anxiety Disorder (up to 12 weeks; dose range of 75 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR (venlafaxine hydrochloride) where the incidence in patients treated with Effexor XR was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Commonly Observed Adverse Events from Tables 3, 4, and 5: Major Depressive Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder (Table 3): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning. Generalized Anxiety Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 4): Abnormalities of sexual function (abnormal ejaculation and impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 Social Anxiety Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for the 2 placebo-controlled trials for the Social Anxiety Disorder indication (Table 5): Asthenia, gastrointestinal complaints (anorexia, dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness, somnolence, dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmic dysfunction, impotence), yawn, sweating, and abnormal vision. Table 3 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Patients with Major Depressive Disorder1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 357) Placebo (n = 285) Body as a Whole Asthenia 8% 7% Cardiovascular System Vasodilatation3 4% 2% Hypertension 4% 1% Digestive System Nausea 31% 12% Constipation 8% 5% Anorexia 8% 4% Vomiting 4% 2% Flatulence 4% 3% Metabolic/Nutritional Weight Loss 3% 0% Nervous System Dizziness 20% 9% Somnolence 17% 8% Insomnia 17% 11% Dry Mouth 12% 6% Nervousness 10% 5% Abnormal Dreams4 7% 2% Tremor 5% 2% Depression 3% <1% Paresthesia 3% 1% Libido Decreased 3% <1% Agitation 3% 1% Respiratory System Pharyngitis 7% 6% Yawn 3% 0% Skin Sweating 14% 3% Special Senses Abnormal Vision5 4% <1% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 % Reporting Event Body System Preferred Term Effexor XR (n = 357) Placebo (n = 285) Urogenital System Abnormal Ejaculation 16% <1% (male)6,7 Impotence7 4% <1% Anorgasmia (female)8,9 3% <1% 1 Incidence, rounded to the nearest %, for events reported by at least 2% of patients treated with Effexor XR, except the following events which had an incidence equal to or less than placebo: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis, and sinusitis. 2 <1% indicates an incidence greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5 Mostly “blurred vision” and “difficulty focusing eyes.” 6 Mostly “delayed ejaculation.” 7 Incidence is based on the number of male patients. 8 Mostly “delayed orgasm” or “anorgasmia.” 9 Incidence is based on the number of female patients. Table 4 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in GAD Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 1381) Placebo (n = 555) Body as a Whole Asthenia 12% 8% Cardiovascular System Vasodilatation3 4% 2% Digestive System Nausea 35% 12% Constipation 10% 4% Anorexia 8% 2% Vomiting 5% 3% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 % Reporting Event Body System Preferred Term Effexor XR (n = 1381) Placebo (n = 555) Nervous System Dizziness 16% 11% Dry Mouth 16% 6% Insomnia 15% 10% Somnolence 14% 8% Nervousness 6% 4% Libido Decreased 4% 2% Tremor 4% <1% Abnormal Dreams4 3% 2% Hypertonia 3% 2% Paresthesia 2% 1% Respiratory System Yawn 3% <1% Skin Sweating 10% 3% Special Senses Abnormal Vision5 5% <1% Urogenital System Abnormal Ejaculation6,7 11% <1% Impotence7 5% <1% Orgasmic Dysfunction (female)8,9 2% 0% 1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, pain, palpitation, pharyngitis, rhinitis, tinnitus, and urinary frequency. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5 Mostly “blurred vision” and “difficulty focusing eyes.” 6 Includes “delayed ejaculation” and “anorgasmia.” 7 Percentage based on the number of males (Effexor XR = 525, placebo = 220). 8 Includes “delayed orgasm,” “abnormal orgasm,” and “anorgasmia.” 9 Percentage based on the number of females (Effexor XR = 856, placebo = 335). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Table 5 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Social Anxiety Disorder Patients1,2 % Reporting Event Body System Effexor XR Placebo Preferred Term (n = 277) (n = 274) Body as a Whole Headache 34% 33% Asthenia 17% 8% Flu Syndrome 6% 5% Accidental Injury 5% 3% Abdominal Pain 4% 3% Cardiovascular System Hypertension 5% 4% Vasodilatation3 3% 1% Palpitation 3% 1% Digestive System Nausea 29% 9% Anorexia4 20% 1% Constipation 8% 4% Diarrhea 6% 5% Vomiting 3% 2% Eructation 2% 0% Metabolic/Nutritional Weight Loss 4% 0% Nervous System Insomnia 23% 7% Dry Mouth 17% 4% Dizziness 16% 8% Somnolence 16% 8% Nervousness 11% 3% Libido Decreased 9% <1% Anxiety 5% 3% Agitation 4% 1% Tremor 4% <1% Abnormal Dreams5 4% <1% Paresthesia 3% <1% Twitching 2% 0% Respiratory System Yawn 5% <1% Sinusitis 2% 1% Skin Sweating 13% 2% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 % Reporting Event Body System Effexor XR Placebo Preferred Term (n = 277) (n = 274) Special Senses Abnormal Vision6 6% 3% Urogenital System Abnormal Ejaculation7,8 16% 1% Impotence8 10% 1% Orgasmic Dysfunction9,10 8% 0% 1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: back pain, depression, dysmenorrhea, dyspepsia, infection, myalgia, pain, pharyngitis, rash, rhinitis, and upper respiratory infection. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “decreased appetite” and “loss of appetite.” 5 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 6 Mostly “blurred vision.” 7 Includes “delayed ejaculation” and “anorgasmia.” 8 Percentage based on the number of males (Effexor XR = 158, placebo = 153). 9 Includes “abnormal orgasm” and “anorgasmia.” 10 Percentage based on the number of females (Effexor XR = 119, placebo = 121). Vital Sign Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 4 beats per minute, compared with an increase of 1 beat per minute for placebo. (See the Sustained Hypertension section of WARNINGS for effects on blood pressure.) In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. Laboratory Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 11.4 mg/dL compared with a mean final decrease of 2.2 mg/dL for placebo. Patients treated with Effexor tablets (the immediate-release form of venlafaxine) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS). Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Tables 3, 4, and 5 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system - Frequent: migraine, postural hypotension, tachycardia; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system - Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT increased, SGPT increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system - Frequent: arthralgia; Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system - Frequent: metrorrhagia,* prostatic disorder (prostatitis and enlarged prostate),* urination impaired, vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea,* menorrhagia,* nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, breast discharge, breast engorgement, balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,* prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm,* vaginal dryness.* *Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, pulmonary eosinophilia, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (eg, development of tolerance, incrementation of dose, drug-seeking behavior). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 OVERDOSAGE Human Experience Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week. There were no reports of acute overdose with Effexor XR in Social Anxiety Disorder trials. Among the patients included in the premarketing evaluation with Effexor, there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 µg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), rhabdomyolysis, seizures, vertigo, and death have been reported. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference(PDR). DOSAGE AND ADMINISTRATION Effexor XR should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water, or it may be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets. Initial Treatment Major Depressive Disorder For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (the immediate release form of venlafaxine), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited. (See PRECAUTIONS-General-Use in Patients with Concomitant Illness.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 Generalized Anxiety Disorder For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) Social Anxiety Disorder (Social Phobia) For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Social Anxiety Disorder, the initial dose of Effexor XR was 75 mg/day and the maximum dose was 225 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in patients with Social Anxiety Disorder was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS). Switching Patients from Effexor Tablets Depressed patients who are currently being treated at a therapeutic dose with Effexor may be switched to Effexor XR at the nearest equivalent dose (mg/day), eg, 37.5 mg venlafaxine two-times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor XR in the third trimester. Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the starting dose be reduced by 50% in patients with moderate hepatic impairment. Because there was much individual variability in clearance between patients with cirrhosis, individualization of dosage may be desirable in some patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50% and that the dose be withheld until the dialysis treatment is completed (4 hrs). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients. Elderly Patients No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, Generalized Anxiety Disorder, or Social Anxiety Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment There is no body of evidence available from controlled trials to indicate how long patients with major depressive disorder, Generalized Anxiety Disorder, or Social Anxiety Disorder should be treated with Effexor XR. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. In patients with Generalized Anxiety Disorder, Effexor XR has been shown to be effective in 6-month clinical trials. The need for continuing medication in patients with GAD who improve with Effexor XR treatment should be periodically reassessed. In patients with Social Anxiety Disorder, there are no efficacy data beyond 12 weeks of treatment with Effexor XR. The need for continuing medication in patients with Social Anxiety Disorder who improve with Effexor XR treatment should be periodically reassessed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 36 Discontinuing Effexor XR Symptoms associated with discontinuation of Effexor XR, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary. Switching Patients To or From a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor XR. In addition, at least 7 days should be allowed after stopping Effexor XR before starting an MAOI (see CONTRAINDICATIONS and WARNINGS). HOW SUPPLIED EffexorXR (venlafaxine hydrochloride) extended-release capsules are available as follows: 37.5 mg, grey cap/peach body with and “Effexor XR” on the cap and “37.5” on the body. NDC 0008-0837-01, bottle of 100 capsules. NDC 0008-0837-03, carton of 10 Redipakblister strips of 10 capsules each. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). 75 mg, peach cap and body with and “Effexor XR” on the cap and “75” on the body. NDC 0008-0833-01, bottle of 100 capsules. NDC 0008-0833-03, carton of 10 Redipakblister strips of 10 capsules each. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). 150 mg, dark orange cap and body with and “Effexor XR” on the cap and “150” on the body. NDC 0008-0836-01, bottle of 100 capsules. NDC 0008-0836-03, carton of 10 Redipakblister strips of 10 capsules each. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). The appearance of these capsules is a trademark of Wyeth Pharmaceuticals. Wyeth Pharmaceuticals Inc. W10404C009 Philadelphia, PA 19101 ET01 Rev 04/04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:50.931555	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20151slr028,030,032,20699slr041,048,052_effexor_lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 30}
12,254	1 Effexor® (venlafaxine hydrochloride) Tablets Rx only Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short- term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS, Pediatric Use.) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Liver Disease In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n =11) subjects (mildly and moderately hepatically impaired, respectively). Venlafaxine oral bioavailability was increased 2–3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long- standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Effexor, for a description of the risks of discontinuation of Effexor). Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor is not approved for use in treating bipolar depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on Effexor, or who have recently had Effexor therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with a monoamine oxidase inhibitor, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. Therefore, it is recommended that Effexor not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Effexor, at least 7 days should be allowed after stopping Effexor before starting an MAOI. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur with Effexor treatment, particularly with concomitant use of serotonergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting diarrhea) (see PRECAUTIONS, Drug Interactions). The concomitant use of Effexor with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Interaction with Monoamine Oxidase Inhibitors). If concomitant treatment of Effexor with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions). The concomitant use of Effexor with serotonin precursors (such as tryptophan supplements) is not recommended (see PRECAUTIONS, Drug Interactions). Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 as treatment-emergent SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine: Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients). PRECAUTIONS General Discontinuation of Treatment with Effexor Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock- like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short- term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety Nervousness Insomnia 6% 13% 18% 3% 6% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies. Changes in Weight Adult Patients: A dose-dependent weight loss was noted in patients treated with venlafaxine for several weeks. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression trials). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor and weight loss agents is not recommended. Effexor is not indicated for weight loss alone or in combination with other products. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia (see PRECAUTIONS, General, Changes in Appetite). The risks associated with longer-term Effexor XR use were assessed in an open-label study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Height Pediatric Patients: During the eight-week placebo-controlled GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). In the six-month open-label study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Appetite Adult Patients: Treatment-emergent anorexia was more commonly reported for venlafaxine- treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. Activation of Mania/Hypomania During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Hyponatremia Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. This should be taken into consideration in patients who are, for example, volume-depleted, elderly, or taking diuretics. Seizures During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Abnormal Bleeding There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor- treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo- controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Effexor. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Mydriasis Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS). Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor and triptans, tramadol, tryptophan supplements or other serotonergic agents (see WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs). Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O- desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole: A pharmacokinetic study with ketoconazole in extensive metabolizers (EM) and poor metabolizers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 and 70% in PM subjects. AUC values for ODV increased by 23% and 141% in EM and PM subjects, respectively. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH- imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH- desipramine levels is unknown. Metoprolol — Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30–40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethyvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor have regular monitoring of blood pressure (see WARNINGS). Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Serotonergic Drugs: Based on the mechanism of action of Effexor and the potential for serotonin syndrome, caution is advised when Effexor is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS, Serotonin Syndrome). If concomitant treatment of Effexor with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). The concomitant use of Effexor with tryptophan supplements is not recommended (see WARNINGS, Serotonin Syndrome). Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis. Pregnancy Teratogenic Effects−Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo- controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess Effexor XR's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with Effexor, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: CNS Venlafaxine Placebo Somnolence Insomnia Dizziness Nervousness Dry mouth Anxiety Gastrointestinal Nausea Urogenital Abnormal ejaculation* Other Headache Asthenia Sweating 3% 3% 3% 2% 2% 2% 6% 3% 3% 2% 2% 1% 1% — — — 1% 1% — 1% — — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor® (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. TABLE 1 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor (n=1033) Placebo (n=609) Body as a Whole Headache Asthenia Infection Chills Chest pain Trauma 25% 12% 6% 3% 2% 2% 24% 6% 5% — 1% 1% Cardiovascular Vasodilatation Increased blood pressure/hypertension Tachycardia Postural hypotension 4% 2% 2% 1% 3% — — — Dermatological Sweating Rash Pruritus 12% 3% 1% 3% 2% — This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 TABLE 1 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor (n=1033) Placebo (n=609) Gastrointestinal Nausea Constipation Anorexia Diarrhea Vomiting Dyspepsia Flatulence 37% 15% 11% 8% 6% 5% 3% 11% 7% 2% 7% 2% 4% 2% Metabolic Weight loss 1% — Nervous System Somnolence Dry mouth Dizziness Insomnia Nervousness Anxiety Tremor Abnormal dreams Hypertonia Paresthesia Libido decreased Agitation Confusion Thinking abnormal Depersonalization Depression Urinary retention Twitching 23% 22% 19% 18% 13% 6% 5% 4% 3% 3% 2% 2% 2% 2% 1% 1% 1% 1% 9% 11% 7% 10% 6% 3% 1% 3% 2% 2% — — 1% 1% — — — — Respiration Yawn 3% — Special Senses Blurred vision Taste perversion Tinnitus Mydriasis 6% 2% 2% 2% 2% — — — This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 TABLE 1 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor (n=1033) Placebo (n=609) Urogenital System Abnormal ejaculation/ orgasm Impotence Urinary frequency Urination impaired Orgasm disturbance 12%2 6%2 3% 2% 2%3 —2 —2 2% — —3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 TABLE 2 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88) Body as a Whole Abdominal pain Asthenia Chills Infection 3.3% 3.3% 1.1% 2.2% 3.4% 16.9% 2.2% 2.2% 2.2% 14.6% 5.6% 5.6% 8.0% 14.8% 6.8% 2.3% Cardiovascular System Hypertension Vasodilatation 1.1% 0.0% 1.1% 4.5% 2.2% 5.6% 4.5% 2.3% Digestive System Anorexia Dyspepsia Nausea Vomiting 2.2% 2.2% 14.1% 1.1% 14.6% 6.7% 32.6% 7.9% 13.5% 6.7% 38.2% 3.4% 17.0% 4.5% 58.0% 6.8% Nervous System Agitation Anxiety Dizziness Insomnia Libido decreased Nervousness Somnolence Tremor 0.0% 4.3% 4.3% 9.8% 1.1% 4.3% 4.3% 0.0% 1.1% 11.2% 19.1% 22.5% 2.2% 21.3% 16.9% 1.1% 2.2% 4.5% 22.5% 20.2% 1.1% 13.5% 18.0% 2.2% 4.5% 2.3% 23.9% 13.6% 5.7% 12.5% 26.1% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 TABLE 2 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88) Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence (Number of men) 0.0% (n=63) 5.8% (n=52) 2.1% (n=48) 3.6% (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry mouth). Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see WARNINGS). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS- General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible- dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 1 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Body as a whole—Frequent: accidental injury, chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia, prostatic disorder (prostatitis and enlarged prostate), vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea, menorrhagia, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, balanitis, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, prolonged erection, gynecomastia (male), hypomenorrhea, kidney calculus, kidney pain, kidney function abnormal, female lactation, mastitis, menopause, oliguria, orchitis, pyelonephritis, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm, vaginal dryness. * Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease (including pulmonary eosinophilia), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (eg, development of tolerance, incrementation of dose, drug- seeking behavior). OVERDOSAGE Human Experience There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI- treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor in the third trimester. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in subjects with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% and the dose be withheld until the dialysis treatment is completed (4 hrs) in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 Discontinuing Effexor (venlafaxine hydrochloride) Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see CONTRAINDICATIONS and WARNINGS). HOW SUPPLIED Effexor® (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “ ” on one side and “701” on scored reverse side. NDC 0008-0701-07, bottle of 30 tablets in unit of use package. NDC 0008-0701-08, bottle of 60 tablets in unit of use package. NDC 0008-0701-01, bottle of 100 tablets. NDC 0008-0701-02, carton of 10 Redipak® blister strips of 10 tablets each. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “ ” on one side and “781” on scored reverse side. NDC 0008-0781-07, bottle of 30 tablets in unit of use package. NDC 0008-0781-08, bottle of 60 tablets in unit of use package. NDC 0008-0781-01, bottle of 100 tablets. NDC 0008-0781-02, carton of 10 Redipak® blister strips of 10 tablets each. 50 mg, peach, shield-shaped tablet with “50” and a “ ” on one side and “703” on scored reverse side. NDC 0008-0703-07, bottle of 30 tablets in unit of use package. NDC 0008-0703-08, bottle of 60 tablets in unit of use package. NDC 0008-0703-01, bottle of 100 tablets. NDC 0008-0703-02, carton of 10 Redipak® blister strips of 10 tablets each. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 75 mg, peach, shield-shaped tablet with “75” and a “ ” on one side and “704” on scored reverse side. NDC 0008-0704-07, bottle of 30 tablets in unit of use package. NDC 0008-0704-08, bottle of 60 tablets in unit of use package. NDC 0008-0704-01, bottle of 100 tablets. NDC 0008-0704-02, carton of 10 Redipak® blister strips of 10 tablets each. 100 mg, peach, shield-shaped tablet with “100” and a “ ” on one side and “705” on scored reverse side. NDC 0008-0705-07, bottle of 20 tablets in unit of use package. NDC 0008-0705-08, bottle of 60 tablets in unit of use package. NDC 0008-0705-01, bottle of 100 tablets. NDC 0008-0705-02, carton of 10 Redipak® blister strips of 10 tablets each. The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20° to 25°C (68 ° to 77°F) in a dry place. Dispense in a well-closed container as defined in the USP. The unit of use package is intended to be dispensed as a unit. U.S. Patent Nos. 4,535,186, 5,916,923, and 6,444,708 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions. 2. How to try to prevent suicidal thoughts or actions in your child. 3. You should watch for certain signs if your child is taking an antidepressant. 4. There are benefits and risks when using antidepressants. 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with: • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 Whenever an antidepressant is started or its dose is changed, pay close attention to your child. After starting an antidepressant, your child should generally see his or her healthcare provider: • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your healthcare provider's advice about how often to come back • More often if problems or questions arise (see Section 3) You should call your child's healthcare provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®).* Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information. * Prozac® is a registered trademark of Eli Lilly and Company Zoloft® is a registered trademark of Pfizer Pharmaceuticals Anafranil® is a registered trademark of Mallinckrodt Inc. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Wyeth® Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 (Update W10402C021) (Update ET01) (Update Rev Date) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Effexor XR® (venlafaxine hydrochloride) Extended-Release Capsules Rx only Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short- term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor XR or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor XR is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS, Pediatric Use.) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. DESCRIPTION Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1- (4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p- methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Effexor XR is formulated as an extended-release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively). Absorption Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for immediate release venlafaxine tablets (Cmax's for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax's were 2 hours for venlafaxine and 3 hours for ODV). When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Metabolism and Excretion Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion. Special Populations Age and Gender: A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Extensive/Poor Metabolizers: Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups. Liver Disease: In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n =11) subjects (mildly and moderately hepatically impaired, respectively). Venlafaxine oral bioavailability was increased 2–3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Renal Disease: In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). Clinical Trials Major Depressive Disorder The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible- dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder. A 12-week study utilizing Effexor XR doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Effexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, Effexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score. A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing Effexor (the immediate release form of venlafaxine) in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of Effexor over placebo. The mean dose in completers was 350 mg/day. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10, and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. Generalized Anxiety Disorder The efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month, placebo- controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in adult outpatients meeting DSM-IV criteria for GAD. One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose. A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg/day dose range utilized in these two studies. Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and the other evaluating Effexor XR doses of 75 to 225 mg/day, showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. Social Anxiety Disorder (Social Phobia) The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in two double-blind, parallel group, 12-week, multicenter, placebo-controlled, flexible-dose studies in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75 to 225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these two trials, Effexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. Panic Disorder The efficacy of Effexor XR capsules as a treatment for panic disorder was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for panic disorder, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study. Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two trials, Effexor XR was significantly more effective than placebo in all three variables. In the two 12-week studies described above, one evaluating Effexor XR doses of 75 and 150 mg/day and the other evaluating Effexor XR doses of 75 and 225 mg/day, efficacy was established for each dose. A dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. In a longer-term study, adult outpatients meeting DSM-IV criteria for panic disorder who had responded during a 12-week open phase with Effexor XR (75 to 225 mg/day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued Effexor XR experienced a significantly longer time to relapse. INDICATIONS AND USAGE Major Depressive Disorder Effexor XR (venlafaxine hydrochloride) extended-release capsules is indicated for the treatment of major depressive disorder. The efficacy of Effexor XR in the treatment of major depressive disorder was established in 8- and 12-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The efficacy of Effexor (the immediate release form of venlafaxine) in the treatment of major depressive disorder in adult inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see Clinical Trials). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied. The efficacy of Effexor XR in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see Clinical Trials). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Generalized Anxiety Disorder Effexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in adult outpatients diagnosed with GAD according to DSM-IV criteria (see Clinical Trials). Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Social Anxiety Disorder Effexor XR is indicated for the treatment of Social Anxiety Disorder, also known as Social Phobia, as defined in DSM-IV (300.23). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. The efficacy of Effexor XR in the treatment of Social Anxiety Disorder was established in two 12-week placebo-controlled trials in adult outpatients with Social Anxiety Disorder (DSM- IV)(see Clinical Trials). The effectiveness of Effexor XR in the long-term treatment of Social Anxiety Disorder, ie, for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Panic Disorder Effexor XR is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, ie, a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) derealization (feelings of unreality) or depersonalization (being detached from oneself); 10) fear of losing control; 11) fear of dying; 12) paresthesias (numbness or tingling sensations); 13) chills or hot flushes. The efficacy of Effexor XR in the treatment of panic disorder was established in two 12-week placebo-controlled trials in adult outpatients with panic disorder (DSM-IV). The efficacy of Effexor XR in prolonging time to relapse in panic disorder among responders following 12 weeks of open-label acute treatment was demonstrated in a placebo-controlled study (see CLINICAL PHARMACOLOGY, Clinical Trials). Nevertheless, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Effexor XR, for a description of the risks of discontinuation of Effexor XR). Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression. Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it is recommended that Effexor XR (venlafaxine hydrochloride) extended-release capsules not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur with Effexor XR treatment, particularly with concomitant use of serotonergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) (see PRECAUTIONS, Drug Interactions). The concomitant use of Effexor XR with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Interaction with Monoamine Oxidase Inhibitors). If concomitant treatment of Effexor XR with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions). The concomitant use of Effexor XR with serotonin precursors (such as tryptophan supplements) is not recommended (see PRECAUTIONS, Drug Interactions). Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. Among patients treated with 75 to 375 mg/day of Effexor XR in premarketing studies in patients with major depressive disorder, 3% (19/705) experienced sustained hypertension [defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive on-therapy visits]. Among patients treated with 37.5 to 225 mg/day of Effexor XR in premarketing GAD studies, 0.5% (5/1011) experienced sustained hypertension. Among patients treated with 75 to 225 mg/day of Effexor XR in premarketing Social Anxiety Disorder studies, 1.4% (4/277) experienced sustained hypertension. Among patients treated with 75 to 225 mg/day of Effexor XR in premarketing panic disorder studies, 0.9% (9/973) experienced sustained hypertension. Experience with the immediate-release venlafaxine showed that sustained hypertension was dose-related, increasing from 3% to 7% at 100 to 300 mg/day to 13% at doses above 300 mg/day. An insufficient number of patients received mean doses of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. In placebo-controlled premarketing studies in patients with major depressive disorder with Effexor XR 75 to 225 mg/day, a final on-drug mean increase in supine diastolic blood pressure (SDBP) of 1.2 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.2 mm Hg for placebo-treated patients. In placebo-controlled premarketing GAD studies with Effexor XR 37.5 to 225 mg/day, up to 8 weeks or up to 6 months, a final on-drug mean increase in SDBP of 0.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.9 and 0.8 mm Hg, respectively, for placebo-treated patients. In placebo-controlled premarketing Social Anxiety Disorder studies with Effexor XR 75 to 225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 1.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 1.3 mm Hg for placebo-treated patients. In placebo-controlled premarketing panic disorder studies with Effexor XR 75 to 225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 0.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 1.1 mm Hg for placebo-treated patients. In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 12 weeks, 0.4% (1/277) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In this patient, the blood pressure increase was modest (13 mm Hg, SDBP). In premarketing panic disorder studies up to 12 weeks, 0.5% (5/1001) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were in a modest range (7 to 19 mm Hg, SDBP). Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 PRECAUTIONS General Discontinuation of Treatment with Effexor XR Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Insomnia and Nervousness Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, GAD, Social Anxiety Disorder, and panic disorder studies, as shown in Table 1. Table 1 Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder, GAD, Social Anxiety Disorder, and Panic Disorder Trials Major Depressive Disorder GAD Social Anxiety Disorder Panic Disorder Symptom Effexor XR n = 357 Placebo n = 285 Effexor XR n = 1381 Placebo n = 555 Effexor XR n = 277 Placebo n = 274 Effexor XR n = 1001 Placebo n = 662 Insomnia Nervousness 17% 10% 11% 5% 15% 6% 10% 4% 23% 11% 7% 3% 17% 4% 9% 6% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in major depressive disorder studies. In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with Effexor XR up to 6 months. In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 3% and 0%, respectively, of the patients treated with Effexor XR up to 12 weeks. In panic disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with Effexor XR up to 12 weeks. Changes in Weight Adult Patients: A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in the short-term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss associated with Effexor XR was 0.1% in major depressive disorder studies. In placebo-controlled GAD studies, a loss of 7% or more of body weight occurred in 3% of Effexor XR patients and 1% of placebo patients who received treatment for up to 6 months. The discontinuation rate for weight loss was 0.3% for patients receiving Effexor XR in GAD studies for up to eight weeks. In placebo-controlled Social Anxiety Disorder trials, 3% of the Effexor XR-treated and 0.4% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving Effexor XR in Social Anxiety Disorder studies discontinued for weight loss. In placebo-controlled panic disorder trials, 3% of the Effexor XR-treated and 2% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving Effexor XR in panic disorder studies discontinued for weight loss. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products. Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). In a 16-week, double-blind, placebo-controlled, flexible dose outpatient trial for Social Anxiety Disorder, Effexor XR-treated patients lost an average of 0.75 kg (n = 137), while placebo-treated patients gained an average of 0.76 kg (n = 148). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in the Social Anxiety Disorder study (47% of Effexor XR-treated patients vs. 14% of placebo-treated patients; p<0.001). Weight loss was not limited to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 patients with treatment-emergent anorexia (see PRECAUTIONS, General, Changes in Appetite). The risks associated with longer-term Effexor XR use were assessed in an open-label MDD study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old). Changes in Height Pediatric Patients: During the eight-week, placebo-controlled GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). During the 16-week, placebo-controlled Social Anxiety Disorder study, both the Effexor XR-treated (n = 109) and the placebo-treated (n = 112) patients each grew an average of 1.0 cm. In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old). Changes in Appetite Adult Patients: Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (4%) in the pool of short-term, double-blind, placebo-controlled major depressive disorder studies. The discontinuation rate for anorexia associated with Effexor XR was 1.0% in major depressive disorder studies. Treatment- emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled GAD studies. The discontinuation rate for anorexia was 0.9% for patients receiving Effexor XR for up to 8 weeks in GAD studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (20%) than placebo-treated patients (2%) in the pool of short-term, double- blind, placebo-controlled Social Anxiety Disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving Effexor XR for up to 12 weeks in Social Anxiety Disorder studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (3%) in the pool of short-term, double-blind, placebo- controlled panic disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving Effexor XR for up to 12 weeks in panic disorder studies. Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. In the placebo-controlled trial for Social Anxiety Disorder, 22% and 3% of patients aged 8-17 treated for up to 16 weeks with Effexor XR and placebo, respectively, reported treatment-emergent anorexia (decreased appetite). The discontinuation rates for anorexia were 0.7% and 0.0% for patients receiving Effexor XR and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 16 placebo, respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either Effexor XR or placebo. Activation of Mania/Hypomania During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of Effexor XR-treated patients and 0.0% placebo patients. In premarketing GAD studies, 0.0% of Effexor XR-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing Social Anxiety Disorder studies, no Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In premarketing panic disorder studies, 0.1% of Effexor XR-treated patients and 0.0% placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with Effexor, mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with 0% of placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Effexor XR should be used cautiously in patients with a history of mania. Hyponatremia Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. This should be taken into consideration in patients who are, for example, volume-depleted, elderly, or taking diuretics. Seizures During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies, or among 277 Effexor XR-treated patients in Social Anxiety Disorder studies. In panic disorder studies, 1 seizure occurred among 1,001 Effexor XR-treated patients. In all premarketing major depressive disorder trials with Effexor, seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures. Abnormal Bleeding There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS-Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Use in Patients With Concomitant Illness Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor XR to patients with diseases or conditions that could affect hemodynamic responses or metabolism. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17 Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received Effexor XR and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder, for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD, for 195 patients who received Effexor XR and 228 patients who received placebo in 12-week double-blind, placebo- controlled trials in Social Anxiety Disorder, and for 661 patients who received Effexor XR and 395 patients who received placebo in three 10- to 12-week double-blind, placebo-controlled trials in panic disorder. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. The mean change from baseline in QTc for Effexor XR-treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 2.8 msec for Effexor XR and decrease of 2.0 msec for placebo). The mean change from baseline in QTc for Effexor XR- treated patients in the panic disorder studies was increased relative to that for placebo-treated patients (increase of 1.5 msec for Effexor XR and decrease of 0.7 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the panic disorder studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and a mean decrease of less than 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. Evaluation of the electrocardiograms for 769 patients who received immediate release Effexor in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 18 In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor XR, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor XR and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Effexor XR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor XR. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities. Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 19 Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor XR and triptans, tramadol, tryptophan supplements or other serotonergic agents (see WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs). Alcohol Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Mydriasis Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS). Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 20 concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Proteins Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion under CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole: A pharmacokinetic study with ketoconazole in extensive metabolizers (EM) and poor metabolizers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects. AUC values for ODV increased by 23% and 141% in EM and PM subjects, respectively. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 21 The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include venlafaxine and any agent(s) that produce simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC's increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. Metoprolol — Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30–40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethyvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure (see WARNINGS). Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 22 CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Serotonergic Drugs: Based on the mechanism of action of Effexor XR and the potential for serotonin syndrome, caution is advised when Effexor XR is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS, Serotonin Syndrome). If concomitant treatment of Effexor XR with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). The concomitant use of Effexor XR with tryptophan supplements is not recommended (see WARNINGS, Serotonin Syndrome). Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor XR with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 23 (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenesis Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose on a mg/m2 basis. Pregnancy Teratogenic Effects - Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 24 Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor XR in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess Effexor XR's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight ). Should the decision be made to treat a pediatric patient with Effexor XR, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation). Geriatric Use Approximately 4% (14/357), 6% (77/1381), 2% (6/277), and 2% (16/1001) of Effexor XR-treated patients in placebo-controlled premarketing major depressive disorder, GAD, Social Anxiety Disorder trials, and panic disorder trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated patients in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 25 The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS The information included in the Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR®, on data up to 12 weeks from a pool of two controlled clinical trials in Social Anxiety Disorder, and on data up to 12 weeks from a pool of four controlled clinical trials in panic disorder. Information on additional adverse events associated with Effexor XR in the entire development program for the formulation and with Effexor (the immediate release formulation of venlafaxine) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR subsection (see also WARNINGS and PRECAUTIONS). Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR Adverse Events Associated with Discontinuation of Treatment Approximately 11% of the 357 patients who received Effexor XR® (venlafaxine hydrochloride) extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 17% of the 277 patients who received Effexor XR capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 274 placebo-treated patients in those studies. Approximately 7% of the 1,001 patients who received Effexor XR capsules in placebo-controlled clinical trials for panic disorder discontinued treatment due to an adverse experience, compared with 6% of the 662 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for any indication) are shown in Table 2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 Table 2 Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials1 Percentage of Patients Discontinuing Due to Adverse Event Adverse Event Major Depressive Disorder Indication2 GAD Indication3,4 Social Anxiety Disorder Indication Panic Disorder Indication Effexor XR n = 357 Placebo n = 285 Effexor XR n = 1381 Placebo n = 555 Effexor XR n = 277 Placebo n = 274 Effexor XR n = 1001 Placebo n = 662 Body as a Whole Asthenia Headache -- -- -- -- 3% -- <1% -- 1% 2% <1% <1% 1% -- 0% -- Digestive System Nausea Anorexia Dry Mouth Vomiting 4% 1% 1% -- <1% <1% 0% -- 8% -- 2% 1% <1% -- <1% <1% 4% -- -- -- 0% -- -- -- 2% -- -- -- <1% -- -- -- Nervous System Dizziness Insomnia Somnolence Nervousness Tremor Anxiety 2% 1% 2% -- -- -- 1% <1% <1% -- -- -- -- 3% 3% 2% 1% -- -- <1% <1% <1% 0% -- 2% 3% 2% -- -- 1% 0% <1% <1% -- -- <1% -- 1% -- -- -- -- -- <1% -- -- -- -- Skin Sweating -- -- 2% <1% 1% 0% -- -- This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 27 Table 2 Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials1 Percentage of Patients Discontinuing Due to Adverse Event Adverse Event Major Depressive Disorder Indication2 GAD Indication3,4 Social Anxiety Disorder Indication Panic Disorder Indication Effexor XR n = 357 Placebo n = 285 Effexor XR n = 1381 Placebo n = 555 Effexor XR n = 277 Placebo n = 274 Effexor XR n = 1001 Placebo n = 662 Urogenital System Impotence -- -- -- -- 3%5 0% -- -- 1 Two of the major depressive disorder studies were flexible dose and one was fixed dose. Four of the GAD studies were fixed dose and one was flexible dose. Both of the Social Anxiety Disorder studies were flexible dose. Two of the panic disorder studies were flexible dose and two were fixed dose. 2 In U.S. placebo-controlled trials for major depressive disorder, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 192], % Placebo [n = 202]): hypertension (1%, <1%); diarrhea (1%, 0%); paresthesia (1%, 0%); tremor (1%, 0%); abnormal vision, mostly blurred vision (1%, 0%); and abnormal, mostly delayed, ejaculation (1%, 0%). 3 In two short-term U.S. placebo-controlled trials for GAD, the following were also common events leading to discontinuation and were considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 476]), % Placebo [n = 201]: headache (4%, <1%); vasodilatation (1%, 0%); anorexia (2%, <1%); dizziness (4%, 1%); thinking abnormal (1%, 0%); and abnormal vision (1%, 0%). 4 In long-term placebo-controlled trials for GAD, the following was also a common event leading to discontinuation and was considered to be drug-related for Effexor XR-treated patients (% Effexor XR [n = 535], % Placebo [n = 257]): decreased libido (1%, 0%). 5 Incidence is based on the number of men (Effexor XR = 158, placebo = 153). Adverse Events Occurring at an Incidence of 2% or More Among Effexor XR-Treated Patients Tables 3, 4, 5, and 6 enumerate the incidence, rounded to the nearest percent, of treatment- emergent adverse events that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day), of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), of Social Anxiety Disorder (up to 12 weeks; dose range of 75 to 225 mg/day), and of panic disorder (up to 12 weeks; dose range of 37.5 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR (venlafaxine hydrochloride) where the incidence in patients treated with Effexor XR was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 28 Commonly Observed Adverse Events from Tables 3, 4, 5, and 6: Major Depressive Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder indication (Table 3): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning. Generalized Anxiety Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 4): Abnormalities of sexual function (abnormal ejaculation and impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating. Social Anxiety Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for the 2 placebo-controlled trials for the Social Anxiety Disorder indication (Table 5): Asthenia, gastrointestinal complaints (anorexia, dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness, somnolence, dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmic dysfunction, impotence), yawn, sweating, and abnormal vision. Panic Disorder Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for 4 placebo-controlled trials for the panic disorder indication (Table 6): gastrointestinal complaints (anorexia, constipation, dry mouth), CNS complaints (somnolence, tremor), abnormalities of sexual function (abnormal ejaculation), and sweating. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 29 Table 3 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Patients with Major Depressive Disorder1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 357) Placebo (n = 285) Body as a Whole Asthenia 8% 7% Cardiovascular System Vasodilatation3 Hypertension 4% 4% 2% 1% Digestive System Nausea Constipation Anorexia Vomiting Flatulence 31% 8% 8% 4% 4% 12% 5% 4% 2% 3% Metabolic/Nutritional Weight Loss 3% 0% Nervous System Dizziness Somnolence Insomnia Dry Mouth Nervousness Abnormal Dreams4 Tremor Depression Paresthesia Libido Decreased Agitation 20% 17% 17% 12% 10% 7% 5% 3% 3% 3% 3% 9% 8% 11% 6% 5% 2% 2% <1% 1% <1% 1% Respiratory System Pharyngitis Yawn 7% 3% 6% 0% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 30 Table 3 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Patients with Major Depressive Disorder1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 357) Placebo (n = 285) Skin Sweating 14% 3% Special Senses Abnormal Vision5 4% <1% Urogenital System Abnormal Ejaculation (male)6,7 Impotence7 Anorgasmia (female)8,9 16% 4% 3% <1% <1% <1% 1 Incidence, rounded to the nearest %, for events reported by at least 2% of patients treated with Effexor XR, except the following events which had an incidence equal to or less than placebo: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis, and sinusitis. 2 <1% indicates an incidence greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5 Mostly “blurred vision” and “difficulty focusing eyes.” 6 Mostly “delayed ejaculation.” 7 Incidence is based on the number of male patients. 8 Mostly “delayed orgasm” or “anorgasmia.” 9 Incidence is based on the number of female patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 31 Table 4 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in GAD Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 1381) Placebo (n = 555) Body as a Whole Asthenia 12% 8% Cardiovascular System Vasodilatation3 4% 2% Digestive System Nausea Constipation Anorexia Vomiting 35% 10% 8% 5% 12% 4% 2% 3% Nervous System Dizziness Dry Mouth Insomnia Somnolence Nervousness Libido Decreased Tremor Abnormal Dreams4 Hypertonia Paresthesia 16% 16% 15% 14% 6% 4% 4% 3% 3% 2% 11% 6% 10% 8% 4% 2% <1% 2% 2% 1% Respiratory System Yawn 3% <1% Skin Sweating 10% 3% Special Senses Abnormal Vision5 5% <1% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 32 Table 4 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in GAD Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 1381) Placebo (n = 555) Urogenital System Abnormal Ejaculation6,7 Impotence7 Orgasmic Dysfunction (female)8,9 11% 5% 2% <1% <1% 0% 1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, pain, palpitation, pharyngitis, rhinitis, tinnitus, and urinary frequency. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5 Mostly “blurred vision” and “difficulty focusing eyes.” 6 Includes “delayed ejaculation” and “anorgasmia.” 7 Percentage based on the number of males (Effexor XR = 525, placebo = 220). 8 Includes “delayed orgasm,” “abnormal orgasm,” and “anorgasmia.” 9 Percentage based on the number of females (Effexor XR = 856, placebo = 335). Table 5 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Social Anxiety Disorder Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 277) Placebo (n = 274) Body as a Whole Headache Asthenia Flu Syndrome Accidental Injury Abdominal Pain 34% 17% 6% 5% 4% 33% 8% 5% 3% 3% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 33 Table 5 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Social Anxiety Disorder Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 277) Placebo (n = 274) Cardiovascular System Hypertension Vasodilatation3 Palpitation 5% 3% 3% 4% 1% 1% Digestive System Nausea Anorexia4 Constipation Diarrhea Vomiting Eructation 29% 20% 8% 6% 3% 2% 9% 1% 4% 5% 2% 0% Metabolic/Nutritional Weight Loss 4% 0% Nervous System Insomnia Dry Mouth Dizziness Somnolence Nervousness Libido Decreased Anxiety Agitation Tremor Abnormal Dreams5 Paresthesia Twitching 23% 17% 16% 16% 11% 9% 5% 4% 4% 4% 3% 2% 7% 4% 8% 8% 3% <1% 3% 1% <1% <1% <1% 0% Respiratory System Yawn Sinusitis 5% 2% <1% 1% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 34 Table 5 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Social Anxiety Disorder Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 277) Placebo (n = 274) Skin Sweating 13% 2% Special Senses Abnormal Vision6 6% 3% Urogenital System Abnormal Ejaculation7,8 Impotence8 Orgasmic Dysfunction9,10 16% 10% 8% 1% 1% 0% 1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: back pain, depression, dysmenorrhea, dyspepsia, infection, myalgia, pain, pharyngitis, rash, rhinitis, and upper respiratory infection. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “decreased appetite” and “loss of appetite.” 5 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 6 Mostly “blurred vision.” 7 Includes “delayed ejaculation” and “anorgasmia.” 8 Percentage based on the number of males (Effexor XR = 158, placebo = 153). 9 Includes “abnormal orgasm” and “anorgasmia.” 10 Percentage based on the number of females (Effexor XR = 119, placebo = 121). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 35 Table 6 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Panic Disorder Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 1001) Placebo (n = 662) Body as a Whole Asthenia 10% 8% Cardiovascular System Hypertension Vasodilatation3 4% 3% 3% 2% Digestive System Nausea Dry mouth Constipation Anorexia4 21% 12% 9% 8% 14% 6% 3% 3% Nervous System Insomnia Somnolence Dizziness Tremor Libido Decreased 17% 12% 11% 5% 4% 9% 6% 10% 2% 2% Skin Sweating 10% 2% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 36 Table 6 Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Effexor XR Clinical Trials in Panic Disorder Patients1,2 % Reporting Event Body System Preferred Term Effexor XR (n = 1001) Placebo (n = 662) Urogenital System Abnormal Ejaculation5,6 Impotence6 Orgasmic Dysfunction7,8 8% 4% 2% <1% <1% <1% 1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, abnormal vision, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, nervousness, pain, paresthesia, pharyngitis, rash, rhinitis, and vomiting. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flushes.” 4 Mostly “decreased appetite” and “loss of appetite.” 5 Includes “delayed or retarded ejaculation” and “anorgasmia.” 6 Percentage based on the number of males (Effexor XR = 335, placebo = 238). 7 Includes “anorgasmia” and “delayed orgasm.” 8 Percentage based on the number of females (Effexor XR = 666, placebo = 424). Vital Sign Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo- controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 4 beats per minute, compared with an increase of 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 1 beat per minute, compared with a decrease of less than 1 beat per minute for placebo. (See the Sustained Hypertension section of WARNINGS for effects on blood pressure.) In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 37 Laboratory Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 11.4 mg/dL compared with a mean final decrease of 2.2 mg/dL for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo. Patients treated with Effexor tablets (the immediate-release form of venlafaxine) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo- treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies, 277 patients in Phase 3 Social Anxiety Disorder studies, and 1314 patients in Phase 3 panic disorder studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 38 experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 6670 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Tables 3, 4, 5, and 6 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system - Frequent: migraine, postural hypotension, tachycardia; Infrequent: angina pectoris, arrhythmia, bradycardia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, hematoma, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor, sinus arrhythmia. Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: abdominal distension, biliary pain, cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, liver tenderness, parotitis, periodontitis, proctitis, rectal disorder, salivary gland enlargement, increased salivation, soft stools, tongue discoloration. Endocrine system - Rare: galactorrhoea, goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura, thrombocytopenia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 39 Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system - Frequent: arthralgia; Infrequent: arthritis, arthrosis, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: bone pain, pathological fracture, muscle cramp, muscle spasms, musculoskeletal stiffness, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor, suicidal ideation; Rare: abnormal/changed behavior, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, libido increased, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, torticollis. Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, psoriasis, urticaria; Rare: brittle nails, erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, miliaria, petechial rash, pruritic rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin hypertrophy, skin striae, sweating decreased. Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: conjunctivitis, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, cataract, chromatopsia, conjunctival edema, corneal lesion, deafness, exophthalmos, eye hemorrhage, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system - Frequent: prostatic disorder (prostatitis, enlarged prostate, and prostate irritability),* urination impaired; Infrequent: albuminuria, amenorrhea,* cystitis, dysuria, hematuria, kidney calculus, kidney pain, leukorrhea,* menorrhagia,* metrorrhagia,* nocturia, breast pain, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage,* vaginitis; Rare: abortion, anuria, breast discharge, breast engorgement, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 40 balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,* bladder pain, prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm,* vaginal dryness.* * Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease (including pulmonary eosinophilia), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 41 While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (eg, development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week. There were no reports of acute overdose with Effexor XR in Social Anxiety Disorder trials. There were 2 reports of acute overdose with Effexor XR in panic disorder trials. One patient took 0.675 g of Effexor XR once, and the other patient took 0.45 g of Effexor XR for 2 days. No signs or symptoms were associated with either overdose, and no actions were taken to treat them. Among the patients included in the premarketing evaluation with Effexor, there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 42 In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR). DOSAGE AND ADMINISTRATION Effexor XR should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water, or it may be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 43 Initial Treatment Major Depressive Disorder For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (the immediate release form of venlafaxine), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited. (See PRECAUTIONS-General-Use in Patients with Concomitant Illness.) Generalized Anxiety Disorder For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) Social Anxiety Disorder (Social Phobia) For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Social Anxiety Disorder, the initial dose of Effexor XR was 75 mg/day and the maximum dose was 225 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in patients with Social Anxiety Disorder was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 44 of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) Panic Disorder It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. In clinical trials establishing the efficacy of Effexor XR in outpatients with panic disorder, initial doses of 37.5 mg/day for 7 days were followed by doses of 75 mg/day and subsequent weekly dose increases of 75 mg/day to a maximum dose of 225 mg/day. Although a dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 7 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) Switching Patients from Effexor Tablets Depressed patients who are currently being treated at a therapeutic dose with Effexor may be switched to Effexor XR at the nearest equivalent dose (mg/day), eg, 37.5 mg venlafaxine two-times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor XR in the third trimester. Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50% and individualization of dosing may be desirable in some patients. Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50% and that the dose be withheld until the dialysis treatment is completed (4 hrs). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 45 Elderly Patients No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, or panic disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment There is no body of evidence available from controlled trials to indicate how long patients with major depressive disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, or panic disorder, should be treated with Effexor XR. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. In patients with Generalized Anxiety Disorder, Effexor XR has been shown to be effective in 6-month clinical trials. The need for continuing medication in patients with GAD who improve with Effexor XR treatment should be periodically reassessed. In patients with Social Anxiety Disorder, there are no efficacy data beyond 12 weeks of treatment with Effexor XR. The need for continuing medication in patients with Social Anxiety Disorder who improve with Effexor XR treatment should be periodically reassessed. In a study of panic disorder in which patients responding during 12 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day), patients continuing Effexor XR experienced a significantly longer time to relapse than patients randomized to placebo. The need for continuing medication in patients with panic disorder who improve with Effexor XR treatment should be periodically reassessed. Discontinuing Effexor XR Symptoms associated with discontinuation of Effexor XR, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 46 rate. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary. Switching Patients To or From a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor XR. In addition, at least 7 days should be allowed after stopping Effexor XR before starting an MAOI (see CONTRAINDICATIONS and WARNINGS). HOW SUPPLIED Effexor XR® (venlafaxine hydrochloride) extended-release capsules are available as follows: 37.5 mg, grey cap/peach body with and “Effexor XR” on the cap and “37.5” on the body. NDC 0008-0837-20, bottle of 15 capsules in unit of use package. NDC 0008-0837-21, bottle of 30 capsules in unit of use package. NDC 0008-0837-22, bottle of 90 capsules in unit of use package. NDC 0008-0837-01, bottle of 100 capsules. NDC 0008-0837-03, carton of 10 Redipak® blister strips of 10 capsules each. 75 mg, peach cap and body with and “Effexor XR” on the cap and “75” on the body. NDC 0008-0833-20, bottle of 15 capsules in unit of use package. NDC 0008-0833-21, bottle of 30 capsules in unit of use package. NDC 0008-0833-22, bottle of 90 capsules in unit of use package. NDC 0008-0833-01, bottle of 100 capsules. NDC 0008-0833-03, carton of 10 Redipak® blister strips of 10 capsules each. 150 mg, dark orange cap and body with and “Effexor XR” on the cap and “150” on the body. NDC 0008-0836-20, bottle of 15 capsules in unit of use package. NDC 0008-0836-21, bottle of 30 capsules in unit of use package. NDC 0008-0836-22, bottle of 90 capsules in unit of use package. NDC 0008-0836-01, bottle of 100 capsules. NDC 0008-0836-03, carton of 10 Redipak® blister strips of 10 capsules each. Store at controlled room temperature, 20° to 25°C (68° to 77°F). The unit of use package is intended to be dispensed as a unit. The appearance of these capsules is a trademark of Wyeth Pharmaceuticals. U.S. Patent Nos. 4,535,186; 5,916,923; 6,274,171; 6,403,120; 6,419,958; and 6,444,708. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 47 Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions. 2. How to try to prevent suicidal thoughts or actions in your child. 3. You should watch for certain signs if your child is taking an antidepressant. 4. There are benefits and risks when using antidepressants. 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with: • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 48 Whenever an antidepressant is started or its dose is changed, pay close attention to your child. After starting an antidepressant, your child should generally see his or her healthcare provider: • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your healthcare provider's advice about how often to come back • More often if problems or questions arise (see Section 3) You should call your child's healthcare provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 49 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®).* Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information. *Prozac® is a registered trademark of Eli Lilly and Company Zoloft® is a registered trademark of Pfizer Pharmaceuticals Anafranil® is a registered trademark of Mallinckrodt Inc. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Wyeth® Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 (Update W10404C025) (Update ET02) (Update Rev Date) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:51.285791	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020151s033,020699s055lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 33}
12,255	Effexor® (venlafaxine hydrochloride) Tablets Rx only Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use) DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. Structural Formula Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Liver Disease In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2-3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo- controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Effexor, for a description of the risks of discontinuation of Effexor). 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor is not approved for use in treating bipolar depression. Potential for Interaction with Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on Effexor, or who have recently had Effexor therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with a monoamine oxidase inhibitor, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. Therefore, it is recommended that Effexor not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Effexor, at least 7 days should be allowed after stopping Effexor before starting an MAOI. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Effexor treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms [e.g., nausea, vomiting diarrhea] (see PRECAUTIONS, Drug Interactions). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Effexor with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Interaction with Monoamine Oxidase Inhibitors). If concomitant treatment of Effexor with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions). The concomitant use of Effexor with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions). Treatment with Effexor and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine: Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients). PRECAUTIONS General Discontinuation of Treatment with Effexor Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short- term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety 6% 3% Nervousness 13% 6% Insomnia 18% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies. Changes in Weight Adult Patients: A dose-dependent weight loss was noted in patients treated with venlafaxine for several weeks. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression trials). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor and weight loss agents is not recommended. Effexor is not indicated for weight loss alone or in combination with other products. Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia (see PRECAUTIONS, General, Changes in Appetite). The risks associated with longer-term Effexor XR use were assessed in an open-label study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (>12 years old). 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Changes in Height Pediatric Patients: During the eight-week placebo-controlled GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). In the six-month open-label study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Appetite Adult Patients: Treatment-emergent anorexia was more commonly reported for venlafaxine treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. Activation of Mania/Hypomania During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of Effexor should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Seizures During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Abnormal Bleeding SSRIs and SNRIs, including Effexor, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor and NSAIDs, aspirin, or other drugs that affect coagulation. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered. Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo- controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Effexor. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day- to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Mydriasis Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS). Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor and triptans, tramadol, tryptophan supplements or other serotonergic agents (see WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs). Patients should be cautioned about the concomitant use of Effexor and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor is initiated or discontinued. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs – 2% to 206%), and AUC values for ODV increased by 23% and 141% in EM and PM subjects (range in PMS – 38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMS and 53% in PMs (range in PMs – 4 to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH desipramine levels is unknown. Metoprolol—Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor have regular monitoring of blood pressure (see WARNINGS). Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Serotonergic Drugs: Based on the mechanism of action of Effexor and the potential for serotonin syndrome, caution is advised when Effexor is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS, Serotonin Syndrome). If concomitant treatment of Effexor with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). The concomitant use of Effexor with tryptophan supplements is not recommended (see WARNINGS, Serotonin Syndrome). Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis. Pregnancy Teratogenic Effects−Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo- controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess Effexor XR's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with Effexor, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation). Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia). The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥ 1%) associated 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: CNS Somnolence Insomnia Dizziness Nervousness Dry mouth Anxiety Gastrointestinal Nausea Urogenital Abnormal ejaculation* Other Headache Asthenia Sweating Venlafaxine 3% 3% 3% 2% 2% 2% 6% 3% 3% 2% 2% Placebo 1% 1% — — — 1% 1% — 1% — — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor® (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Body as a Whole Headache Asthenia Infection Chills Chest pain Trauma Cardiovascular Vasodilatation Increased blood pressure/hypertension Tachycardia Postural hypotension Dermatological Sweating Rash Pruritus Gastrointestinal Nausea Constipation Anorexia Diarrhea Vomiting Dyspepsia Flatulence Metabolic Weight loss 25% 12% 6% 3% 2% 2% 4% 2% 2% 1% 12% 3% 1% 37% 15% 11% 8% 6% 5% 3% 1% 24% 6% 5% — 1% 1% 3% — — — 3% 2% — 11% 7% 2% 7% 2% 4% 2% — 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Nervous System Somnolence Dry mouth Dizziness Insomnia Nervousness Anxiety Tremor Abnormal dreams Hypertonia Paresthesia Libido decreased Agitation Confusion Thinking abnormal Depersonalization Depression Urinary retention Twitching Respiration Yawn Special Senses Blurred vision Taste perversion Tinnitus Mydriasis 23% 22% 19% 18% 13% 6% 5% 4% 3% 3% 2% 2% 2% 2% 1% 1% 1% 1% 3% 6% 2% 2% 2% 9% 11% 7% 10% 6% 3% 1% 3% 2% 2% — — 1% 1% — — — — — 2% — — — 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda —2 —2 2% — —3 TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Urogenital System Abnormal ejaculation/ orgasm 12%2 Impotence 6%2 Urinary frequency 3% Urination impaired 2% Orgasm disturbance 2%3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo 75 225 375 (n=92) (n=89) (n=89) (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% Cardiovascular System Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo 75 225 375 (n=92) (n=89) (n=89) (n=88) Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% (Number of men) (n=63) (n=52) (n=48) (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry mouth). Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see WARNINGS). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase in 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible- dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 2 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole—Frequent: accidental injury, chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia, prostatic disorder (prostatitis and enlarged prostate), vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea, menorrhagia, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, balanitis, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, prolonged erection, gynecomastia (male), hypomenorrhea, kidney calculus, kidney pain, kidney function abnormal, female lactation, mastitis, menopause, oliguria, orchitis, pyelonephritis, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm, vaginal dryness. * Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (eg, development of tolerance, incrementation of dose, drug- seeking behavior). OVERDOSAGE Human Experience There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI- treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor in the third trimester. 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Discontinuing Effexor (venlafaxine hydrochloride) Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. 32 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see CONTRAINDICATIONS and WARNINGS). HOW SUPPLIED Effexor® (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “ ” on one side and “701” on scored reverse side. NDC 0008-0701-07, bottle of 30 tablets in unit of use package. NDC 0008-0701-08, bottle of 60 tablets in unit of use package. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “ ” on one side and “781” on scored reverse side. NDC 0008-0781-07, bottle of 30 tablets in unit of use package. NDC 0008-0781-08, bottle of 60 tablets in unit of use package. 50 mg, peach, shield-shaped tablet with “50” and a “ ” on one side and “703” on scored reverse side. NDC 0008-0703-07, bottle of 30 tablets in unit of use package. NDC 0008-0703-08, bottle of 60 tablets in unit of use package. 75 mg, peach, shield-shaped tablet with “75” and a “ ” on one side and “704” on scored reverse side. NDC 0008-0704-07, bottle of 30 tablets in unit of use package. NDC 0008-0704-08, bottle of 60 tablets in unit of use package. 100 mg, peach, shield-shaped tablet with “100” and a “ ” on one side and “705” on scored reverse side. NDC 0008-0705-07, bottle of 20 tablets in unit of use package. NDC 0008-0705-08, bottle of 60 tablets in unit of use package. The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20° to 25°C (68° to 77°F) in a dry place. Dispense in a well-closed container as defined in the USP. The unit of use package is intended to be dispensed as a unit. U.S. Patent Nos. 4,535,186, 5,916,923, and 6,444,708 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • trouble sleeping (insomnia) • attempts to commit suicide • new or worse irritability • new or worse depression • acting aggressive, being angry, or violent 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • new or worse anxiety • acting on dangerous impulses • feeling very agitated or restless • an extreme increase in activity and talking (mania) • panic attacks • other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. C P U Logo This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Telephone Illustration Wyeth® Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 (Update W10402C031) (Update ET01) (Update Rev Date) 35 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:51.369626	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020151s054lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 54}
12,256	Effexor® (venlafaxine hydrochloride) Tablets Rx only Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use) DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. structural formula Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol: water (0.2 M sodium chloride) partition coefficient is 0.43. 1 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based 2 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Liver Disease In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2-3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and 3 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in 4 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. The use of MAOIs intended to treat psychiatric disorders with Effexor or within 7 days of stopping treatment with Effexor is contraindicated because of an increased risk of serotonin syndrome. The use of Effexor within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). Starting Effexor in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION). WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short- term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 5 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, 6 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Discontinuation of Treatment with Effexor, for a description of the risks of discontinuation of Effexor). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor is not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Effexor, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Effexor with MAOIs intended to treat psychiatric disorders is contraindicated. Effexor should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor. Effexor should be discontinued before 7 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of Effexor with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk of serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Effexor and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive visits) revealed a dose- dependent increase in the incidence of sustained hypertension for venlafaxine: Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Mydriasis 8 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients). PRECAUTIONS General Discontinuation of Treatment with Effexor Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short- term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety 6% 3% Nervousness 13% 6% Insomnia 18% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies. 9 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Changes in Weight Adult Patients: A dose-dependent weight loss was noted in patients treated with venlafaxine for several weeks. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression trials). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor and weight loss agents is not recommended. Effexor is not indicated for weight loss alone or in combination with other products. Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia (see PRECAUTIONS, General, Changes in Appetite). The risks associated with longer-term Effexor XR use were assessed in an open-label study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Height Pediatric Patients: During the eight-week placebo-controlled GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). In the six-month open-label study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Appetite Adult Patients: Treatment-emergent anorexia was more commonly reported for venlafaxine treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with 10 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment- emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. Activation of Mania/Hypomania During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of Effexor should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Seizures During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Abnormal Bleeding SSRIs and SNRIs, including Effexor, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor and NSAIDs, aspirin, or other drugs that affect coagulation. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled 11 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda trials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered. Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo- controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. Information for Patients 12 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Effexor. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Mydriasis Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS). Concomitant Medication 13 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor and triptans, tramadol, tryptophan supplements or other serotonergic agents (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs, Serotonergic Drugs). Patients should be cautioned about the concomitant use of Effexor and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. 14 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor is initiated or discontinued. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. 15 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ketoconazole: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMS and 53% in PMs (range in PMs 4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2 OH-desipramine levels is unknown. Metoprolol—Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. 16 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor have regular monitoring of blood pressure (see WARNINGS). Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. (see CONTRAINDICATIONS and WARNINGS) Serotonergic Drugs: Based on the mechanism of action of Effexor and the potential for serotonin syndrome, caution is advised when Effexor is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort and methylene blue (see CONTRAINDICATIONS and WARNINGS, 17 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serotonin Syndrome). If concomitant treatment of Effexor with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome). The concomitant use of Effexor with tryptophan supplements is not recommended (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome). Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. 18 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Impairment of Fertility Reproduction and fertility studies of venlafaxine in rats showed no adverse effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mg/day on a mg/m2 basis. However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mg/day. Pregnancy Teratogenic Effects−Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS- Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 19 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo- controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess Effexor XR’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with Effexor, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation). Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia). The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥ 1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: 20 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS Venlafaxine Placebo Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% — Nervousness 2% — Dry mouth 2% — Anxiety 2% 1% Gastrointestinal Nausea 6% 1% Urogenital Abnormal ejaculation* 3% — Other Headache 3% 1% Asthenia 2% — Sweating 2% — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor® (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. 21 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo- Controlled Clinical Trials1 Effexor Placebo Body System Preferred Term (n=1033) (n=609) Body as a Whole Headache 25% 24% Asthenia 12% 6% Infection 6% 5% Chills 3% — Chest pain 2% 1% Trauma 2% 1% Cardiovascular Vasodilatation 4% 3% Increased blood pressure/hypertension 2% — Tachycardia 2% — Postural hypotension 1% — Dermatological Sweating 12% 3% Rash 3% 2% Pruritus 1% — Gastrointestinal Nausea 37% 11% Constipation 15% 7% Anorexia 11% 2% Diarrhea 8% 7% Vomiting 6% 2% Dyspepsia 5% 4% Flatulence 3% 2% Metabolic Weight loss 1% — Nervous System Somnolence 23% 9% Dry mouth 22% 11% Dizziness 19% 7% Insomnia 18% 10% Nervousness 13% 6% Anxiety 6% 3% Tremor 5% 1% Abnormal dreams 4% 3% Hypertonia 3% 2% Paresthesia 3% 2% Libido decreased 2% — Agitation 2% — 22 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo- Controlled Clinical Trials1 Effexor Placebo Body System Preferred Term (n=1033) (n=609) Confusion 2% 1% Thinking abnormal 2% 1% Depersonalization 1% — Depression 1% — Urinary retention 1% — Twitching 1% — Respiration Yawn 3% — Special Senses Blurred vision 6% 2% Taste perversion 2% — Tinnitus 2% — Mydriasis 2% — Urogenital System Abnormal ejaculation/ orgasm 12%2 —2 Impotence 6%2 —2 Urinary frequency 3% 2% Urination impaired 2% — Orgasm disturbance 2%3 —3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. 23 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% Cardiovascular System Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% 24 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88) (Number of men) (n=63) (n=52) (n=48) (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., dizziness and nausea), but less to other effects (e.g., abnormal ejaculation and dry mouth). Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see WARNINGS). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats 25 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda per minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 2 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole—Frequent: accidental injury, chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor. 26 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, 27 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia, prostatic disorder (prostatitis and enlarged prostate), vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea, menorrhagia, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, balanitis, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, prolonged erection, gynecomastia (male), hypomenorrhea, kidney calculus, kidney pain, kidney function abnormal, female lactation, mastitis, menopause, oliguria, orchitis, pyelonephritis, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm, vaginal dryness. * Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. 28 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI- treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor should be written for the 29 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects 30 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Discontinuing Effexor (venlafaxine hydrochloride) Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. 31 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Effexor. Conversely, at least 7 days should be allowed after stopping Effexor before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Effexor With Other MAOls, Such as Linezolid or Methylene Blue: Do not start Effexor in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). In some cases, a patient already receiving therapy with Effexor may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Effexor should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Effexor may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Effexor is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). HOW SUPPLIED Effexor® (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “W” on one side and “701” on scored reverse side. NDC 0008-0701-08, bottle of 60 tablets in unit of use package. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “W” on one side and “781” on scored reverse side. NDC 0008-0781-08, bottle of 60 tablets in unit of use package. 50 mg, peach, shield-shaped tablet with “50” and a “W” on one side and “703” on scored reverse side. NDC 0008-0703-07, bottle of 30 tablets in unit of use package. 75 mg, peach, shield-shaped tablet with “75” and a “W” on one side and “704” on scored reverse side. 32 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 0008-0704-07, bottle of 30 tablets in unit of use package. 100 mg, peach, shield-shaped tablet with “100” and a “W” on one side and “705” on scored reverse side. NDC 0008-0705-07, bottle of 20 tablets in unit of use package. The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20° to 25°C (68° to 77°F) in a dry place. Dispense in a well-closed container as defined in the USP. The unit of use package is intended to be dispensed as a unit. company logo LAB-0465-3.0 Revised December 2012 33 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide EFFEXOR (e-fex-or) (venlafaxine hydrochloride) (Tablets) Read the Medication Guide that comes with EFFEXOR before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about EFFEXOR? EFFEXOR and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions:  EFFEXOR and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.  Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.  Watch for these changes and call your healthcare provider right away if you notice:  New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.  Pay particular attention to such changes when EFFEXOR is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:  attempts to commit suicide  acting on dangerous impulses  acting aggressive or violent  thoughts about suicide or dying  new or worse depression  new or worse anxiety or panic attacks  feeling agitated, restless, angry or irritable  trouble sleeping  an increase in activity or talking more than what is normal for you  other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. EFFEXOR may be associated with these serious side effects: 2. Serotonin Syndrome This condition can be life-threatening and may include:  agitation, hallucinations, coma or other changes in mental status 34 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  coordination problems or muscle twitching (overactive reflexes)  racing heartbeat, high or low blood pressure  sweating or fever  nausea, vomiting, or diarrhea  muscle rigidity 3. Changes in blood pressure. EFFEXOR may:  increase your blood pressure. Control high blood pressure before starting treatment and monitor blood pressure regularly 4. Enlarged pupils (mydriasis). 5. Anxiety and insomnia. 6. Changes in appetite or weight.  children and adolescents should have height and weight monitored during treatment 7. Manic/hypomanic episodes:  greatly increased energy  severe trouble sleeping  racing thoughts  reckless behavior  unusually grand ideas  excessive happiness or irritability  talking more or faster than usual 8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:  headache  weakness or feeling unsteady  confusion, problems concentrating or thinking or memory problems 9. Seizures or convulsions. 10. Abnormal bleeding: EFFEXOR and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti- inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 11. Elevated cholesterol. 12. Lung disease and pneumonia: EFFEXOR may cause rare lung problems. Symptoms include:  worsening shortness of breath  cough  chest discomfort 13. Severe allergic reactions:  trouble breathing  swelling of the face, tongue, eyes or mouth  rash, itchy welts (hives) or blisters, alone or with fever or joint pain Do not stop EFFEXOR without first talking to your healthcare provider. Stopping EFFEXOR too quickly or changing from another antidepressant too quickly may cause serious symptoms including:  anxiety, irritability  feeling tired, restless or problems sleeping  headache, sweating, dizziness  electric shock-like sensations, shaking, confusion, nightmares  vomiting, nausea, diarrhea What is EFFEXOR? EFFEXOR is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Talk to your healthcare provider if you do not think that your condition is getting better with EFFEXOR XR treatment. Who should not take EFFEXOR? Do not take EFFEXOR if you:  are allergic to EFFEXOR or any of the ingredients in EFFEXOR. See the end of this Medication Guide for a complete list of ingredients in EFFEXOR. 35 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  have uncontrolled narrow-angle glaucoma  take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.  Do not take an MAOI within 7 days of stopping EFFEXOR unless directed to do so by your physician.  Do not start EFFEXOR if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take EFFEXOR close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:  high fever  uncontrolled muscle spasms  stiff muscles  rapid changes in heart rate or blood pressure  confusion  loss of consciousness (pass out) What should I tell my healthcare provider before taking EFFEXOR? Ask if you are not sure. Before starting EFFEXOR, tell your healthcare provider if you:  Are taking certain drugs such as:  Medicines used to treat migraine headaches such as: o triptans  Medicines used to treat mood, anxiety, psychotic or thought disorders, such as: o tricyclic antidepressants o lithium o SSRIs o SNRIs o antipsychotic drugs  Medicines used to treat pain such as: o tramadol  Medicines used to thin your blood such as: o warfarin  Medicines used to treat heartburn such as: o Cimetidine  Over-the-counter medicines or supplements such as: o Aspirin or other NSAIDs o Tryptophan o St. John’s Wort  have heart problems  have diabetes  have liver problems  have kidney problems  have thyroid problems  have glaucoma  have or had seizures or convulsions  have bipolar disorder or mania  have low sodium levels in your blood  have high blood pressure  have high cholesterol  have or had bleeding problems  are pregnant or plan to become pregnant. It is not known if EFFEXOR will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy  are breast-feeding or plan to breast- feed. Some EFFEXOR may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking EFFEXOR. Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. EFFEXOR and some medicines may interact with each other, 36 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take EFFEXOR with your other medicines. Do not start or stop any medicine while taking EFFEXOR without talking to your healthcare provider first. If you take EFFEXOR, you should not take any other medicines that contain (venlafaxine) including: venlafaxine HCl. How should I take EFFEXOR?  Take EFFEXOR exactly as prescribed. Your healthcare provider may need to change the dose of EFFEXOR until it is the right dose for you.  EFFEXOR is to be taken with food.  If you miss a dose of EFFEXOR, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of EFFEXOR at the same time.  If you take too much EFFEXOR, call your healthcare provider or poison control center right away, or get emergency treatment.  When switching from another antidepressant to EFFEXOR your doctor may want to lower the dose of the initial antidepressant first to avoid side effects What should I avoid while taking EFFEXOR? EFFEXOR can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how EFFEXOR affects you. Do not drink alcohol while using EFFEXOR. What are the possible side effects of EFFEXOR? EFFEXOR may cause serious side effects, including:  See “What is the most important information I should know about EFFEXOR?”  Increased cholesterol- have your cholesterol checked regularly  Newborns whose mothers take EFFEXOR in the third trimester may have problems right after birth including:  problems feeding and breathing  seizures  shaking, jitteriness or constant crying  Narrow-angle glaucoma/enlarged pupils. Check eye pressure regularly if you:  have a history of increased eye pressure  are at risk for certain types of glaucoma Common possible side effects in people who take EFFEXOR include:  unusual dreams  sexual problems  loss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouth  feeling tired, fatigued or overly sleepy  change in sleep habits, problems sleeping  yawning  tremor or shaking  dizziness, blurred vision  sweating  feeling anxious, nervous or jittery  headache 37 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  increase in heart rate Medication Guide. Do not use EFFEXOR Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of EFFEXOR. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800 FDA-1088. How should I store EFFEXOR?  Store EFFEXOR at room temperature between 68°F and 77°F (20°C to 25°C).  Keep EFFEXOR in a dry place. Keep EFFEXOR and all medicines out of the reach of children. General information about EFFEXOR Medicines are sometimes prescribed for purposes other than those listed in a for a condition for which it was not prescribed. Do not give EFFEXOR to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about EFFEXOR. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about EFFEXOR that is written for healthcare professionals. For more information about EFFEXOR call 1-800-934-5556. What are the ingredients in EFFEXOR? Active ingredient: (venlafaxine) Inactive ingredients:  Tablets: cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com company logo LAB-0568-2.0 Revised December 2012 38 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:51.918723	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020151s031s055s058s060lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 55}
12,257	Effexor® (venlafaxine hydrochloride) Tablets Rx only Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use) DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. Structural Formula Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Liver Disease In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2-3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Effexor must not be used concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with SNRI or SSRI treatment or with other serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see DOSAGE AND ADMINISTRATION). WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo- controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Effexor, for a description of the risks of discontinuation of Effexor). 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor is not approved for use in treating bipolar depression. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Effexor treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms [e.g., nausea, vomiting diarrhea] (see PRECAUTIONS, Drug Interactions). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Effexor with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS). If concomitant treatment of Effexor with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions). The concomitant use of Effexor with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions). 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment with Effexor and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine: Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients). 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Discontinuation of Treatment with Effexor Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short- term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety 6% 3% Nervousness 13% 6% Insomnia 18% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Changes in Weight Adult Patients: A dose-dependent weight loss was noted in patients treated with venlafaxine for several weeks. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression trials). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor and weight loss agents is not recommended. Effexor is not indicated for weight loss alone or in combination with other products. Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia (see PRECAUTIONS, General, Changes in Appetite). The risks associated with longer-term Effexor XR use were assessed in an open-label study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Height Pediatric Patients: During the eight-week placebo-controlled GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). In the six-month open-label study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Appetite Adult Patients: Treatment-emergent anorexia was more commonly reported for venlafaxine treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. Activation of Mania/Hypomania During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of Effexor should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Seizures During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Abnormal Bleeding SSRIs and SNRIs, including Effexor, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor and NSAIDs, aspirin, or other drugs that affect coagulation. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda trials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered. Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo- controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Effexor. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day- to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Mydriasis Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS). 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor and triptans, tramadol, tryptophan supplements or other serotonergic agents (see WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs). Patients should be cautioned about the concomitant use of Effexor and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor is initiated or discontinued. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ketoconazole: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMS and 53% in PMs (range in PMs 4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH desipramine levels is unknown. Metoprolol—Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor have regular monitoring of blood pressure (see WARNINGS). Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Serotonergic Drugs: Based on the mechanism of action of Effexor and the potential for serotonin syndrome, caution is advised when Effexor is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS, Serotonin Syndrome). If concomitant treatment of Effexor with these drugs is 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). The concomitant use of Effexor with tryptophan supplements is not recommended (see WARNINGS, Serotonin Syndrome). Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis. 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Teratogenic Effects−Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo- controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor in a child or adolescent must balance the potential risks with the clinical need. 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Although no studies have been designed to primarily assess Effexor XR's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with Effexor, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation). Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia). The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥ 1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS Somnolence Insomnia Dizziness Nervousness Dry mouth Anxiety Gastrointestinal Nausea Urogenital Abnormal ejaculation* Other Headache Asthenia Sweating Venlafaxine 3% 3% 3% 2% 2% 2% 6% 3% 3% 2% 2% Placebo 1% 1% — — — 1% 1% — 1% — — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor® (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor Placebo (n=1033) (n=609) Body as a Whole Headache Asthenia Infection Chills Chest pain Trauma Cardiovascular Vasodilatation Increased blood pressure/hypertension Tachycardia Postural hypotension Dermatological Sweating Rash Pruritus Gastrointestinal Nausea Constipation Anorexia Diarrhea Vomiting Dyspepsia Flatulence Metabolic Weight loss Nervous System Somnolence Dry mouth Dizziness Insomnia Nervousness Anxiety Tremor Abnormal dreams 25% 12% 6% 3% 2% 2% 4% 2% 2% 1% 12% 3% 1% 37% 15% 11% 8% 6% 5% 3% 1% 23% 22% 19% 18% 13% 6% 5% 4% 24% 6% 5% — 1% 1% 3% — — — 3% 2% — 11% 7% 2% 7% 2% 4% 2% — 9% 11% 7% 10% 6% 3% 1% 3% 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1 Body System Preferred Term Effexor (n=1033) Placebo (n=609) Hypertonia Paresthesia Libido decreased Agitation Confusion Thinking abnormal Depersonalization Depression Urinary retention Twitching 3% 3% 2% 2% 2% 2% 1% 1% 1% 1% 2% 2% — — 1% 1% — — — — Respiration Yawn 3% — Special Senses Blurred vision Taste perversion Tinnitus Mydriasis 6% 2% 2% 2% 2% — — — Urogenital System Abnormal ejaculation/ orgasm 12%2 —2 Impotence 6%2 —2 Urinary frequency 3% 2% Urination impaired 2% — Orgasm disturbance 2%3 —3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo 75 225 375 (n=92) (n=89) (n=89) (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% Cardiovascular System Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo 75 225 375 (n=92) (n=89) (n=89) (n=88) Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% (Number of men) (n=63) (n=52) (n=48) (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry mouth). Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see WARNINGS). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible- dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 2 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Body as a whole—Frequent: accidental injury, chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia, prostatic disorder (prostatitis and enlarged prostate), vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea, menorrhagia, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, balanitis, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, prolonged erection, gynecomastia (male), hypomenorrhea, kidney calculus, kidney pain, kidney function abnormal, female lactation, mastitis, menopause, oliguria, orchitis, pyelonephritis, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm, vaginal dryness. * Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (eg, development of tolerance, incrementation of dose, drug- seeking behavior). OVERDOSAGE Human Experience There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI- treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor in the third trimester. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Discontinuing Effexor (venlafaxine hydrochloride) Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see CONTRAINDICATIONS). HOW SUPPLIED Effexor® (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “ W ” on one side and “701” on scored reverse side. NDC 0008-0701-08, bottle of 60 tablets in unit of use package. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “ W ” on one side and “781” on scored reverse side. NDC 0008-0781-08, bottle of 60 tablets in unit of use package. 50 mg, peach, shield-shaped tablet with “50” and a “ W ” on one side and “703” on scored reverse side. NDC 0008-0703-07, bottle of 30 tablets in unit of use package. 75 mg, peach, shield-shaped tablet with “75” and a “ W ” on one side and “704” on scored reverse side. NDC 0008-0704-07, bottle of 30 tablets in unit of use package. NDC 0008-0704-08, bottle of 60 tablets in unit of use package. 100 mg, peach, shield-shaped tablet with “100” and a “ W ” on one side and “705” on scored reverse side. NDC 0008-0705-07, bottle of 20 tablets in unit of use package. NDC 0008-0705-08, bottle of 60 tablets in unit of use package. The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20° to 25°C (68° to 77°F) in a dry place. 32 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dispense in a well-closed container as defined in the USP. The unit of use package is intended to be dispensed as a unit. U.S. Patent Nos. 5,916,923, 6,310,101 and 6,444,708 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • trouble sleeping (insomnia) • attempts to commit suicide • new or worse irritability • new or worse depression • acting aggressive, being angry, or violent • new or worse anxiety • acting on dangerous impulses • feeling very agitated or restless • an extreme increase in activity and talking (mania) • panic attacks • other unusual changes in behavior or mood Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. 35 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CPU GraphicPhone Graphic This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Wyeth® Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 (Update W10402C034) (Update ET01) (Update Rev Date) 36 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:51.978796	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020151s056s057lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 57}
12,258	Effexor® (venlafaxine hydrochloride) Tablets Rx only Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use) DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. structural formula Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol: water (0.2 M sodium chloride) partition coefficient is 0.43. 1 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based 2 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Liver Disease In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2-3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and 3 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in 4 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. The use of MAOIs intended to treat psychiatric disorders with Effexor or within 7 days of stopping treatment with Effexor is contraindicated because of an increased risk of serotonin syndrome. The use of Effexor within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). Starting Effexor in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION). WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short- term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 5 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, 6 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Discontinuation of Treatment with Effexor, for a description of the risks of discontinuation of Effexor). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor is not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Effexor, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Effexor with MAOIs intended to treat psychiatric disorders is contraindicated. Effexor should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor. Effexor should be discontinued before 7 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of Effexor with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk of serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Effexor and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive visits) revealed a dose- dependent increase in the incidence of sustained hypertension for venlafaxine: Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Mydriasis 8 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients). PRECAUTIONS General Discontinuation of Treatment with Effexor Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short- term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety 6% 3% Nervousness 13% 6% Insomnia 18% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies. 9 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Changes in Weight Adult Patients: A dose-dependent weight loss was noted in patients treated with venlafaxine for several weeks. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression trials). The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor and weight loss agents is not recommended. Effexor is not indicated for weight loss alone or in combination with other products. Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia (see PRECAUTIONS, General, Changes in Appetite). The risks associated with longer-term Effexor XR use were assessed in an open-label study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Height Pediatric Patients: During the eight-week placebo-controlled GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). In the six-month open-label study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Appetite Adult Patients: Treatment-emergent anorexia was more commonly reported for venlafaxine treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with 10 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment- emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. Activation of Mania/Hypomania During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of Effexor should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Seizures During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Abnormal Bleeding SSRIs and SNRIs, including Effexor, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor and NSAIDs, aspirin, or other drugs that affect coagulation. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled 11 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda trials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered. Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo- controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. Information for Patients 12 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Effexor. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Mydriasis Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS). Concomitant Medication 13 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor and triptans, tramadol, tryptophan supplements or other serotonergic agents (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs, Serotonergic Drugs). Patients should be cautioned about the concomitant use of Effexor and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. 14 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor is initiated or discontinued. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. 15 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ketoconazole: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMS and 53% in PMs (range in PMs 4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2 OH-desipramine levels is unknown. Metoprolol—Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. 16 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor have regular monitoring of blood pressure (see WARNINGS). Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. (see CONTRAINDICATIONS and WARNINGS) Serotonergic Drugs: Based on the mechanism of action of Effexor and the potential for serotonin syndrome, caution is advised when Effexor is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort and methylene blue (see CONTRAINDICATIONS and WARNINGS, 17 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serotonin Syndrome). If concomitant treatment of Effexor with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome). The concomitant use of Effexor with tryptophan supplements is not recommended (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome). Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. 18 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Impairment of Fertility Reproduction and fertility studies of venlafaxine in rats showed no adverse effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mg/day on a mg/m2 basis. However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mg/day. Pregnancy Teratogenic Effects−Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS- Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 19 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo- controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess Effexor XR’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with Effexor, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation). Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia). The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥ 1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: 20 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS Venlafaxine Placebo Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% — Nervousness 2% — Dry mouth 2% — Anxiety 2% 1% Gastrointestinal Nausea 6% 1% Urogenital Abnormal ejaculation* 3% — Other Headache 3% 1% Asthenia 2% — Sweating 2% — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor® (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. 21 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo- Controlled Clinical Trials1 Effexor Placebo Body System Preferred Term (n=1033) (n=609) Body as a Whole Headache 25% 24% Asthenia 12% 6% Infection 6% 5% Chills 3% — Chest pain 2% 1% Trauma 2% 1% Cardiovascular Vasodilatation 4% 3% Increased blood pressure/hypertension 2% — Tachycardia 2% — Postural hypotension 1% — Dermatological Sweating 12% 3% Rash 3% 2% Pruritus 1% — Gastrointestinal Nausea 37% 11% Constipation 15% 7% Anorexia 11% 2% Diarrhea 8% 7% Vomiting 6% 2% Dyspepsia 5% 4% Flatulence 3% 2% Metabolic Weight loss 1% — Nervous System Somnolence 23% 9% Dry mouth 22% 11% Dizziness 19% 7% Insomnia 18% 10% Nervousness 13% 6% Anxiety 6% 3% Tremor 5% 1% Abnormal dreams 4% 3% Hypertonia 3% 2% Paresthesia 3% 2% Libido decreased 2% — Agitation 2% — 22 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo- Controlled Clinical Trials1 Effexor Placebo Body System Preferred Term (n=1033) (n=609) Confusion 2% 1% Thinking abnormal 2% 1% Depersonalization 1% — Depression 1% — Urinary retention 1% — Twitching 1% — Respiration Yawn 3% — Special Senses Blurred vision 6% 2% Taste perversion 2% — Tinnitus 2% — Mydriasis 2% — Urogenital System Abnormal ejaculation/ orgasm 12%2 —2 Impotence 6%2 —2 Urinary frequency 3% 2% Urination impaired 2% — Orgasm disturbance 2%3 —3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. 23 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% Cardiovascular System Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% 24 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88) (Number of men) (n=63) (n=52) (n=48) (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., dizziness and nausea), but less to other effects (e.g., abnormal ejaculation and dry mouth). Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see WARNINGS). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats 25 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda per minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 2 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole—Frequent: accidental injury, chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor. 26 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, 27 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia, prostatic disorder (prostatitis and enlarged prostate), vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea, menorrhagia, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, balanitis, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, prolonged erection, gynecomastia (male), hypomenorrhea, kidney calculus, kidney pain, kidney function abnormal, female lactation, mastitis, menopause, oliguria, orchitis, pyelonephritis, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm, vaginal dryness. * Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. 28 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE Human Experience There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI- treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor should be written for the 29 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects 30 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Discontinuing Effexor (venlafaxine hydrochloride) Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. 31 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Effexor. Conversely, at least 7 days should be allowed after stopping Effexor before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Effexor With Other MAOls, Such as Linezolid or Methylene Blue: Do not start Effexor in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). In some cases, a patient already receiving therapy with Effexor may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Effexor should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Effexor may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Effexor is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). HOW SUPPLIED Effexor® (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “W” on one side and “701” on scored reverse side. NDC 0008-0701-08, bottle of 60 tablets in unit of use package. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “W” on one side and “781” on scored reverse side. NDC 0008-0781-08, bottle of 60 tablets in unit of use package. 50 mg, peach, shield-shaped tablet with “50” and a “W” on one side and “703” on scored reverse side. NDC 0008-0703-07, bottle of 30 tablets in unit of use package. 75 mg, peach, shield-shaped tablet with “75” and a “W” on one side and “704” on scored reverse side. 32 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 0008-0704-07, bottle of 30 tablets in unit of use package. 100 mg, peach, shield-shaped tablet with “100” and a “W” on one side and “705” on scored reverse side. NDC 0008-0705-07, bottle of 20 tablets in unit of use package. The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20° to 25°C (68° to 77°F) in a dry place. Dispense in a well-closed container as defined in the USP. The unit of use package is intended to be dispensed as a unit. company logo LAB-0465-3.0 Revised December 2012 33 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide EFFEXOR (e-fex-or) (venlafaxine hydrochloride) (Tablets) Read the Medication Guide that comes with EFFEXOR before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about EFFEXOR? EFFEXOR and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions:  EFFEXOR and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.  Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.  Watch for these changes and call your healthcare provider right away if you notice:  New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.  Pay particular attention to such changes when EFFEXOR is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:  attempts to commit suicide  acting on dangerous impulses  acting aggressive or violent  thoughts about suicide or dying  new or worse depression  new or worse anxiety or panic attacks  feeling agitated, restless, angry or irritable  trouble sleeping  an increase in activity or talking more than what is normal for you  other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. EFFEXOR may be associated with these serious side effects: 2. Serotonin Syndrome This condition can be life-threatening and may include:  agitation, hallucinations, coma or other changes in mental status 34 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  coordination problems or muscle twitching (overactive reflexes)  racing heartbeat, high or low blood pressure  sweating or fever  nausea, vomiting, or diarrhea  muscle rigidity 3. Changes in blood pressure. EFFEXOR may:  increase your blood pressure. Control high blood pressure before starting treatment and monitor blood pressure regularly 4. Enlarged pupils (mydriasis). 5. Anxiety and insomnia. 6. Changes in appetite or weight.  children and adolescents should have height and weight monitored during treatment 7. Manic/hypomanic episodes:  greatly increased energy  severe trouble sleeping  racing thoughts  reckless behavior  unusually grand ideas  excessive happiness or irritability  talking more or faster than usual 8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:  headache  weakness or feeling unsteady  confusion, problems concentrating or thinking or memory problems 9. Seizures or convulsions. 10. Abnormal bleeding: EFFEXOR and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti- inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 11. Elevated cholesterol. 12. Lung disease and pneumonia: EFFEXOR may cause rare lung problems. Symptoms include:  worsening shortness of breath  cough  chest discomfort 13. Severe allergic reactions:  trouble breathing  swelling of the face, tongue, eyes or mouth  rash, itchy welts (hives) or blisters, alone or with fever or joint pain Do not stop EFFEXOR without first talking to your healthcare provider. Stopping EFFEXOR too quickly or changing from another antidepressant too quickly may cause serious symptoms including:  anxiety, irritability  feeling tired, restless or problems sleeping  headache, sweating, dizziness  electric shock-like sensations, shaking, confusion, nightmares  vomiting, nausea, diarrhea What is EFFEXOR? EFFEXOR is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Talk to your healthcare provider if you do not think that your condition is getting better with EFFEXOR XR treatment. Who should not take EFFEXOR? Do not take EFFEXOR if you:  are allergic to EFFEXOR or any of the ingredients in EFFEXOR. See the end of this Medication Guide for a complete list of ingredients in EFFEXOR. 35 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  have uncontrolled narrow-angle glaucoma  take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.  Do not take an MAOI within 7 days of stopping EFFEXOR unless directed to do so by your physician.  Do not start EFFEXOR if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take EFFEXOR close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:  high fever  uncontrolled muscle spasms  stiff muscles  rapid changes in heart rate or blood pressure  confusion  loss of consciousness (pass out) What should I tell my healthcare provider before taking EFFEXOR? Ask if you are not sure. Before starting EFFEXOR, tell your healthcare provider if you:  Are taking certain drugs such as:  Medicines used to treat migraine headaches such as: o triptans  Medicines used to treat mood, anxiety, psychotic or thought disorders, such as: o tricyclic antidepressants o lithium o SSRIs o SNRIs o antipsychotic drugs  Medicines used to treat pain such as: o tramadol  Medicines used to thin your blood such as: o warfarin  Medicines used to treat heartburn such as: o Cimetidine  Over-the-counter medicines or supplements such as: o Aspirin or other NSAIDs o Tryptophan o St. John’s Wort  have heart problems  have diabetes  have liver problems  have kidney problems  have thyroid problems  have glaucoma  have or had seizures or convulsions  have bipolar disorder or mania  have low sodium levels in your blood  have high blood pressure  have high cholesterol  have or had bleeding problems  are pregnant or plan to become pregnant. It is not known if EFFEXOR will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy  are breast-feeding or plan to breast- feed. Some EFFEXOR may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking EFFEXOR. Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. EFFEXOR and some medicines may interact with each other, 36 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take EFFEXOR with your other medicines. Do not start or stop any medicine while taking EFFEXOR without talking to your healthcare provider first. If you take EFFEXOR, you should not take any other medicines that contain (venlafaxine) including: venlafaxine HCl. How should I take EFFEXOR?  Take EFFEXOR exactly as prescribed. Your healthcare provider may need to change the dose of EFFEXOR until it is the right dose for you.  EFFEXOR is to be taken with food.  If you miss a dose of EFFEXOR, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of EFFEXOR at the same time.  If you take too much EFFEXOR, call your healthcare provider or poison control center right away, or get emergency treatment.  When switching from another antidepressant to EFFEXOR your doctor may want to lower the dose of the initial antidepressant first to avoid side effects What should I avoid while taking EFFEXOR? EFFEXOR can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how EFFEXOR affects you. Do not drink alcohol while using EFFEXOR. What are the possible side effects of EFFEXOR? EFFEXOR may cause serious side effects, including:  See “What is the most important information I should know about EFFEXOR?”  Increased cholesterol- have your cholesterol checked regularly  Newborns whose mothers take EFFEXOR in the third trimester may have problems right after birth including:  problems feeding and breathing  seizures  shaking, jitteriness or constant crying  Narrow-angle glaucoma/enlarged pupils. Check eye pressure regularly if you:  have a history of increased eye pressure  are at risk for certain types of glaucoma Common possible side effects in people who take EFFEXOR include:  unusual dreams  sexual problems  loss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouth  feeling tired, fatigued or overly sleepy  change in sleep habits, problems sleeping  yawning  tremor or shaking  dizziness, blurred vision  sweating  feeling anxious, nervous or jittery  headache 37 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  increase in heart rate Medication Guide. Do not use EFFEXOR Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of EFFEXOR. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800 FDA-1088. How should I store EFFEXOR?  Store EFFEXOR at room temperature between 68°F and 77°F (20°C to 25°C).  Keep EFFEXOR in a dry place. Keep EFFEXOR and all medicines out of the reach of children. General information about EFFEXOR Medicines are sometimes prescribed for purposes other than those listed in a for a condition for which it was not prescribed. Do not give EFFEXOR to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about EFFEXOR. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about EFFEXOR that is written for healthcare professionals. For more information about EFFEXOR call 1-800-934-5556. What are the ingredients in EFFEXOR? Active ingredient: (venlafaxine) Inactive ingredients:  Tablets: cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com company logo LAB-0568-2.0 Revised December 2012 38 Reference ID: 3229485 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:52.086036	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020151s031s055s058s060lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 58}
12,259	Effexor® (venlafaxine hydrochloride) Tablets Rx only Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use) DESCRIPTION Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. chemical structure Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. 1 Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens. Age and Gender A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based 2 upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Liver Disease In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2-3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION). Renal Disease In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION). CLINICAL TRIALS The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and 3 Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. INDICATIONS AND USAGE Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in 4 sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Effexor must not be used concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with SNRI or SSRI treatment or with other serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see DOSAGE AND ADMINISTRATION). WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short- term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 5 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, 6 Discontinuation of Treatment with Effexor, for a description of the risks of discontinuation of Effexor). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor is not approved for use in treating bipolar depression. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Effexor treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs, eg, methylene blue), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms [e.g., nausea, vomiting diarrhea] (see PRECAUTIONS, Drug Interactions). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Effexor with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS). If concomitant treatment of Effexor with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions). The concomitant use of Effexor with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions). 7 Treatment with Effexor and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Sustained Hypertension Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive visits) revealed a dose- dependent increase in the incidence of sustained hypertension for venlafaxine: Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine < 100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% > 300 mg/day 13% Placebo 2% An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Mydriasis Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients). PRECAUTIONS General Discontinuation of Treatment with Effexor Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and 8 retrospective surveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Anxiety and Insomnia Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short- term, double-blind, placebo-controlled depression studies: Venlafaxine Placebo Symptom n = 1033 n = 609 Anxiety 6% 3% Nervousness 13% 6% Insomnia 18% 10% Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies. Changes in Weight Adult Patients: A dose-dependent weight loss was noted in patients treated with venlafaxine for several weeks. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression trials). 9 The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor and weight loss agents is not recommended. Effexor is not indicated for weight loss alone or in combination with other products. Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia (see PRECAUTIONS, General, Changes in Appetite). The risks associated with longer-term Effexor XR use were assessed in an open-label study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Height Pediatric Patients: During the eight-week placebo-controlled GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). In the six-month open-label study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (>12 years old). Changes in Appetite Adult Patients: Treatment-emergent anorexia was more commonly reported for venlafaxine treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment- emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. Activation of Mania/Hypomania During Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. 10 As with all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of Effexor should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Seizures During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Abnormal Bleeding SSRIs and SNRIs, including Effexor, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor and NSAIDs, aspirin, or other drugs that affect coagulation. Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered. 11 Use in Patients with Concomitant Illness Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo- controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Effexor. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. 12 Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor therapy does not adversely affect their ability to engage in such activities. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Mydriasis Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS). Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor and triptans, tramadol, tryptophan supplements or other serotonergic agents (see WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs). Patients should be cautioned about the concomitant use of Effexor and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that 13 interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Alcohol Although Effexor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Effexor. Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% 14 when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor is initiated or discontinued. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV 15 increased on average by approximately 23% in EMS and 53% in PMs (range in PMs 4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems. Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2 OH-desipramine levels is unknown. Metoprolol—Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor have regular monitoring of blood pressure (see WARNINGS). Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral 16 dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS. CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Serotonergic Drugs: Based on the mechanism of action of Effexor and the potential for serotonin syndrome, caution is advised when Effexor is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort and methylene blue (see WARNINGS, Serotonin Syndrome). If concomitant treatment of Effexor with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). The concomitant use of Effexor with tryptophan supplements is not recommended (see WARNINGS, Serotonin Syndrome). Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). 17 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine. Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor treatment. Postmarketing Spontaneous Drug Interaction Reports See ADVERSE REACTIONS, Postmarketing Reports. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Mutagenicity Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose. Impairment of Fertility Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis. Pregnancy Teratogenic Effects−Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup 18 deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS- Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Labor and Delivery The effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo- controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess Effexor XR’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with Effexor, regular monitoring of weight and height is recommended during 19 treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation). Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia). The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events (≥ 1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: CNS Venlafaxine Placebo Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% — Nervousness 2% — Dry mouth 2% — Anxiety 2% 1% Gastrointestinal Nausea 6% 1% Urogenital Abnormal ejaculation* 3% — Other Headache 3% 1% 20 Asthenia 2% — Sweating 2% — * Percentages based on the number of males. — Less than 1% Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of Effexor® (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men. Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo- Controlled Clinical Trials1 Effexor Placebo Body System Preferred Term (n=1033) (n=609) Body as a Whole Headache 25% 24% Asthenia 12% 6% Infection 6% 5% Chills 3% — Chest pain 2% 1% Trauma 2% 1% Cardiovascular Vasodilatation 4% 3% Increased blood pressure/hypertension 2% — Tachycardia 2% — 21 TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo- Controlled Clinical Trials1 Effexor Placebo Body System Preferred Term (n=1033) (n=609) Postural hypotension 1% — Dermatological Sweating 12% 3% Rash 3% 2% Pruritus 1% — Gastrointestinal Nausea 37% 11% Constipation 15% 7% Anorexia 11% 2% Diarrhea 8% 7% Vomiting 6% 2% Dyspepsia 5% 4% Flatulence 3% 2% Metabolic Weight loss 1% — Nervous System Somnolence 23% 9% Dry mouth 22% 11% Dizziness 19% 7% Insomnia 18% 10% Nervousness 13% 6% Anxiety 6% 3% Tremor 5% 1% Abnormal dreams 4% 3% Hypertonia 3% 2% Paresthesia 3% 2% Libido decreased 2% — Agitation 2% — Confusion 2% 1% Thinking abnormal 2% 1% Depersonalization 1% — Depression 1% — Urinary retention 1% — Twitching 1% — Respiration Yawn 3% — Special Senses Blurred vision 6% 2% 22 TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo- Controlled Clinical Trials1 Effexor Placebo Body System Preferred Term (n=1033) (n=609) Taste perversion 2% — Tinnitus 2% — Mydriasis 2% — Urogenital System Abnormal ejaculation/ orgasm 12%2 —2 Impotence 6%2 —2 Urinary frequency 3% 2% Urination impaired 2% — Orgasm disturbance 2%3 —3 1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3. — Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation. TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% 23 TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial Effexor (mg/day) Body System/ Preferred Term Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88) Cardiovascular System Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory System Yawn 0.0% 4.5% 5.6% 8.0% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% (Number of men) (n=63) (n=52) (n=48) (n=56) Adaptation to Certain Adverse Events Over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry mouth). 24 Vital Sign Changes Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see WARNINGS). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose and titration 25 studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 2 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole—Frequent: accidental injury, chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis. Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, 26 SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia, prostatic disorder (prostatitis and enlarged prostate), vaginitis; Infrequent: albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea, menorrhagia, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage; Rare: abortion, anuria, balanitis, breast discharge, breast engorgement, breast enlargement, endometriosis, fibrocystic breast, calcium crystalluria, cervicitis, ovarian cyst, prolonged erection, gynecomastia (male), hypomenorrhea, kidney calculus, kidney pain, kidney function abnormal, female lactation, mastitis, menopause, oliguria, orchitis, pyelonephritis, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm, vaginal dryness. 27 * Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Effexor (venlafaxine hydrochloride) is not a controlled substance. Physical and Psychological Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION). While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Effexor (eg, development of tolerance, incrementation of dose, drug-seeking behavior). 28 OVERDOSAGE Human Experience There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI- treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. 29 In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Effexor in the third trimester. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. 30 Dosage for Elderly Patients No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Maintenance Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Discontinuing Effexor (venlafaxine hydrochloride) Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see CONTRAINDICATIONS). HOW SUPPLIED Effexor® (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with “25” and a “W” on one side and “701” on scored reverse side. NDC 0008-0701-08, bottle of 60 tablets in unit of use package. 37.5 mg, peach, shield-shaped tablet with “37.5” and a “W” on one side and “781” on scored reverse side. NDC 0008-0781-08, bottle of 60 tablets in unit of use package. 31 50 mg, peach, shield-shaped tablet with “50” and a “W” on one side and “703” on scored reverse side. NDC 0008-0703-07, bottle of 30 tablets in unit of use package. 75 mg, peach, shield-shaped tablet with “75” and a “W” on one side and “704” on scored reverse side. NDC 0008-0704-07, bottle of 30 tablets in unit of use package. 100 mg, peach, shield-shaped tablet with “100” and a “W” on one side and “705” on scored reverse side. NDC 0008-0705-07, bottle of 20 tablets in unit of use package. The appearance of these tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20° to 25°C (68° to 77°F) in a dry place. Dispense in a well-closed container as defined in the USP. The unit of use package is intended to be dispensed as a unit. U.S. Patent Nos. 5,916,923, 6,310,101 and 6,444,708 Pfizer logo LAB-0465-2.0 Revised March 2012 32 Medication Guide Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:  all risks and benefits of treatment with antidepressant medicines  all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?  Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.  Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.  Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: 33  thoughts about suicide or dying  trouble sleeping (insomnia)  attempts to commit suicide  new or worse irritability  new or worse depression  acting aggressive, being angry, or violent  new or worse anxiety  acting on dangerous impulses  feeling very agitated or restless  an extreme increase in activity and talking (mania)  panic attacks  other unusual changes in behavior or mood Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What else do I need to know about antidepressant medicines?  Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.  Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.  Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.  Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.  Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. computer This product’s label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. telephonePfizer logo 34 LAB-0568-1.0 Revised November 2011 35	custom-source	2025-02-12T13:46:52.170691	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020151s059lbl.pdf', 'application_number': 20151, 'submission_type': 'SUPPL ', 'submission_number': 59}
12,260	Attachment 1 Page 1 Class Suicidality Labeling Language for Antidepressants [This section should be located at the beginning of the package insert with bolded font and enclosed in a black box] [Insert established name] Suicidality in Children and Adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Insert established name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. [Insert established name] is not approved for use in pediatric patients. (See Warnings and Precautions: Pediatric Use) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. [This section should be located under WARNINGS. Please note that the title of this section should be bolded, and it should be the first paragraph in this section.] WARNINGS-Clinical Worsening and Suicide Risk Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. A causal role for antidepressants in inducing suicidality has been established in pediatric patients. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 1 Page 2 There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for [Insert established name] should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 1 Page 3 above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established name] is not approved for use in treating bipolar depression. [This section should be located under PRECAUTIONS, Information for Patients.] Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with [Insert established name] and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Adolescents is available for [Insert established name]. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking [Insert established name]. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. [This section should be located under PRECAUTIONS, Pediatric Use.] Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 286 pediatric patients with MDD have been conducted with Serzone, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Serzone in a child or adolescent must balance the potential risks with the clinical need. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 1 Medication Guide About Using Antidepressants in Children and Teenagers What is the most important information I should know if my child is being prescribed an antidepressant? Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant: 1. There is a risk of suicidal thoughts or actions 2. How to try to prevent suicidal thoughts or actions in your child 3. You should watch for certain signs if your child is taking an antidepressant 4. There are benefits and risks when using antidepressants 1. There is a Risk of Suicidal Thoughts or Actions Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal. A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal. For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with • Bipolar illness (sometimes called manic-depressive illness) • A family history of bipolar illness • A personal or family history of attempting suicide If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant. 2. How to Try to Prevent Suicidal Thoughts and Actions To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for. Whenever an antidepressant is started or its dose is changed, pay close attention to your child. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 2 After starting an antidepressant, your child should generally see his or her healthcare provider: • Once a week for the first 4 weeks • Every 2 weeks for the next 4 weeks • After taking the antidepressant for 12 weeks • After 12 weeks, follow your healthcare provider's advice about how often to come back • More often if problems or questions arise (see other side) You should call your child's healthcare provider between visits if needed. 3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher: • Thoughts about suicide or dying • Attempts to commit suicide • New or worse depression • New or worse anxiety • Feeling very agitated or restless • Panic attacks • Difficulty sleeping (insomnia) • New or worse irritability • Acting aggressive, being angry, or violent • Acting on dangerous impulses • An extreme increase in activity and talking • Other unusual changes in behavior or mood Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms. 4. There are Benefits and Risks When Using Antidepressants Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Other side effects can occur with antidepressants (see section below). Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric depression. For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) . This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Attachment 2 Page 3 Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members. Is this all I need to know if my child is being prescribed an antidepressant? No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:52.243327	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20152s035lbl.pdf', 'application_number': 20152, 'submission_type': 'SUPPL ', 'submission_number': 35}
12,262	ApprovletS037.doc (clean copy 27March02) Page 4 of 39 Rx only VIDEX (didanosine) VIDEX (didanosine) Chewable/Dispersible Buffered Tablets VIDEX (didanosine) Buffered Powder for Oral Solution VIDEX (didanosine) Pediatric Powder for Oral Solution (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK. (SEE WARNINGS AND PRECAUTIONS: PREGNANCY.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 5 of 39 DESCRIPTION VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate. VIDEX Buffered Powder for Oral Solution is supplied for oral administration in single-dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively. Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine). The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25°C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37°C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 6 of 39 MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 7 of 39 Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established. CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of VIDEX and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 8 of 39 Table 1: Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients Pediatric Patientsb Parameter Adult Patientsa n 8 months to 19 years n 2 weeks to 4 months n Oral bioavailability (%) 42 ± 12 6 25 ± 20 46 ND Apparent volume of distributionc (L/m2) 43.70 ± 8.90 6 28 ± 15 49 ND CSF-plasma ratiod 21 ± 0.03%e 5 46% (range 12-85%) 7 ND Systemic clearancec (mL/min/m2) 526 ± 64.7 6 516 ± 184 49 ND Renal clearancef (mL/min/m2) 223 ± 85.0 6 240 ± 90 15 ND Apparent oral clearanceg (mL/min/m2) 1252 ± 154 6 2064 ± 736 48 1353 ± 759 41 Elimination half-lifef (h) 1.5 ± 0.4 6 0.8 ± 0.3 60 1.2 ± 0.3 21 Urinary recovery of didanosinef (%) 18 ± 8 6 18 ± 10 15 ND CSF = cerebrospinal fluid, ND = not determined. a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2. b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half- life was 2.0 ± 0.7 h. c Following IV administration. d Following IV administration in adults and IV or oral administration in pediatric patients. e Mean ± SE. f Following oral administration. g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral bioavailability estimate. Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (CMAX) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.) Special Populations Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 9 of 39 adults indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. Table 2: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose Creatinine Clearance (mL/min) Parameter ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 NDa CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 a ND = not determined due to anuria CLcr = creatinine clearance CL/F = apparent oral clearance CLR = renal clearance Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children above 8 months old. For information on controlled clinical studies in pediatric patients, see PRECAUTIONS, Pediatric Use and Clinical Studies. Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age. Gender: The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95% confidence interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 10 of 39 pharmacokinetic interactions were observed. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions. Table 3: Results of Drug Interaction Studies: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑312% ↑232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑113% ↑69% ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8a ↓16% ↓28% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑111% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↔ ↓17% (-27, - 7%)b ↔ ↓13% (-28, 5%)b ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↔ ↓12% methadone, chronic maintenance dose 200 mg single dose 16,10c ↓57% ↓66% No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) loperamide, 4 mg q6h for 1 day 300 mg single dose 12a ↔ ↓23% metoclopramide, 10 mg single dose 300 mg single dose 12a ↔ ↑13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↑14% ↑13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑13% (-1, 27%) ↑17% (-4, 38%) ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓13% (0, 23%) ↓16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↔ ↑17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↔ ↔ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 11 of 39 Table 3: Results of Drug Interaction Studies: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b 90% CI. c Parallel-group design; entries are subjects receiving combination and control regimens, respectively. NA Not available. Table 4: Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) ciprofloxacin 750 mg q12h for 3 days, 2 h before didanosine 750 mg single dose 200 mg q12h for 3 days buffered placebo tablet 8a 12 ↓26% ↓98% ↓16% ↓93% delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h 12a 12a ↓32% ↑20% ↓53% ↑18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12a ↓21% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↓84% ↓11% ↓82% ↓4% ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↓14% ↓20% nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑12% ↔ No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days 6a ↔ ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↔ ↑17% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 12 of 39 Table 4: Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓11% (-17, -4%) ↓12% (-28, 8%) trimethoprim, 200 mg single dose 200 mg single dose 8a ↑10% (-9, 34%) ↓22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓10% (-27, 11%) ↓16.5% (-53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. NA Not available. INDICATIONS AND USAGE VIDEX in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection (see Clinical Studies). Clinical Studies Combination Therapy START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and increases in CD4 cell counts through 48 weeks. Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks are shown in Figure 1 and Table 5. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 13 of 39 Figure 1: Treatment Response Through Week 48, AI454-148 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original study medication (except stavudine-zidovudine switches), and have not experienced an AIDS-defining event. Table 5: Outcomes of Randomized Treatment through Week 48, AI454-148 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX/stavudine/nelfinavir lamivudine/zidovudine/nelfinavir Week 48 Status n=503 n=253 Responder a 50* (34) 59 (47) Virologic failureb 36 (57) 32 (48) Death or disease progression <1 (<1) 1 (<1) Discontinued due to adverse events 4 (2) 2 (<1) Discontinued due to other reasonsc 6 (3) 4 (2) Never initiated treatment 4 (4) 2 (2) <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test. a Patients achieved virologic response [two consecutive viral load <400 (<50) copies/mL] and maintained it to Week 48. b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48. c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy. Monotherapy The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease 0 20 40 60 80 100 0 8 16 24 32 40 48 Study Week Percent of patients ] < 400 c/mL ] < 50 c/mL VIDEX+stavudine+nelfinavir (n=503) zidovudine+lamivudine+nelfinavir (n=253) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 14 of 39 progression or death was similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were similar between the treatment groups. Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death compared with those treated with zidovudine alone. Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including VIDEX, was time limited. CONTRAINDICATION VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulations. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 15 of 39 indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX use should be suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when administering VIDEX to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 16 of 39 PRECAUTIONS Frequency of Dosing The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see Clinical Studies). VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. General Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain the following quantities of phenylalanine: Table 6 All Strengths Phenylalanine per 2-tablet dose 73 mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 17 of 39 Table 6 All Strengths Phenylalanine per tablet 36.5 mg Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains 1380 mg sodium. Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to patients with significant renal impairment, particularly after prolonged dosing. Patients with Hepatic Impairment: It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (See Patient Information Leaflet.) Patients should be informed that a serious toxicity of VIDEX used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 18 of 39 with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX may be required if toxicity develops. Patients should be informed that when VIDEX is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when VIDEX is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX toxicities. Patients should be advised that to ensure proper acid neutralization in the stomach they must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the risk of gastrointestinal side effects from excess antacid, patients should take no more than four VIDEX tablets at each dose. VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX. Patients should be advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX are unknown at this time. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3 and 4). The clinical recommendations based on the results of these studies are listed in Table 7. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 19 of 39 Table 7: Established Drug Interactions with VIDEX Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ciprofloxacin ↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin. delavirdine ↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine. ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. indinavir ↓ indinavir concentration Administer VIDEX 1 hour after indinavir. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX. ↑ indicates increase. ↓ indicates decrease. Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX formulations either contain buffers or are mixed with antacids before administration, interactions may be anticipated with drugs whose absorption can be affected by the level of acidity in the stomach and with drugs that have been demonstrated to interact with antacids containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in Table 8. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 20 of 39 Table 8: Predicted Drug Interactions with VIDEX Use with Caution, Risk of Adverse Reactions May Be Increased Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Antacids containing magnesium or aluminum ↑ side effects associated with antacid components Use caution with VIDEX Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution. Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX Drug Class Effect Clinical Comment Azole antifungals ↓ ketoconazole or itraconazole concentration Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX. Quinolone antibiotics (see also ciprofloxacin in Table 7) ↓ quinolone concentration Consult package insert of the quinolone. Tetracycline antibiotics ↓ antibiotic concentration Consult package insert of the tetracycline. ↑ indicates increase. ↓ indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 21 of 39 Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 22 of 39 Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast- feed if they are receiving VIDEX. Pediatric Use Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients (see Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. Geriatric Use In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 23 of 39 ADVERSE REACTIONS A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When VIDEX is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when VIDEX is used alone. Thus, patients treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with stavudine may also be at increased risk for peripheral neuropathy (see PRECAUTIONS). Adults: Selected clinical adverse events that occurred in adult patients in clinical studies with VIDEX are provided in Tables 9 and 10. Table 9: Selected Clinical Adverse Events from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 VIDEX zidovudine VIDEX zidovudine Adverse Events n=197 n=212 n=298 n=304 Diarrhea 19 15 28 21 Peripheral Neurologic Symptoms/Neuropathy 17 14 20 12 Rash/Pruritus 7 8 9 5 Abdominal Pain 13 8 7 8 Pancreatitis 7 3 6 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 24 of 39 Table 10: Selected Clinical Adverse Events from Combination Studies Percent of Patientsa AI454-148b START 2b VIDEX + stavudine + nelfinavir zidovudine + lamivudine + nelfinavir VIDEX + stavudine + indinavir zidovudine + lamivudine + indinavir Adverse Events n=482 n=248 n=102 n=103 Diarrhea 70 60 45 39 Nausea 28 40 53 67 Headache 21 30 46 37 Peripheral Neurologic Symptoms/Neuropathy 26 6 21 10 Rash 13 16 30 18 Vomiting 12 14 30 35 Pancreatitis (see below) 1 * <1 * a Percentages based on treated subjects. b Median duration of treatment 48 weeks. * This event was not observed in this study arm. Pancreatitis resulting in death was observed in one patient who received VIDEX plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose. Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 11-13. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 25 of 39 Table 11: Selected Laboratory Abnormalities from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 VIDEX zidovudine VIDEX zidovudine Parameter n=197 n=212 n=298 n=304 SGOT (AST) (>5 x ULN) 9 4 7 6 SGPT (ALT) (>5 x ULN) 9 6 6 6 Alkaline phosphatase (>5 x ULN) 4 1 1 1 Amylase (≥1.4 x ULN) 17 12 15 5 Uric acid (>12 mg/dL) 3 1 2 1 ULN = upper limit of normal. Table 12: Selected Laboratory Abnormalities from Combination Studies (Grades 3-4) Percent of Patientsa AI454-148b START 2b VIDEX + stavudine + nelfinavir zidovudine + lamivudine + nelfinavir VIDEX + stavudine + indinavir zidovudine + lamivudine + indinavir Parameter n=482 n=248 n=102 n=103 Bilirubin (>2.6 x ULN) <1 <1 16 8 SGOT (AST) (>5 x ULN) 3 2 7 7 SGPT (ALT) (>5 x ULN) 3 3 8 5 GGT (>5 x ULN) NC NC 5 2 Lipase (>2 x ULN) 7 2 5 5 Amylase (>2 x ULN) NC NC 8 2 ULN = upper limit of normal. NC=Not Collected a Percentages based on treated subjects. b Median duration of treatment 48 weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 26 of 39 Table 13: Selected Laboratory Abnormalities from Combination Studies (All Grades) Percent of Patientsa I454-148b START 2b VIDEX + stavudine + nelfinavir zidovudine + lamivudine + nelfinavir VIDEX + stavudine + indinavir zidovudine + lamivudine + indinavir Parameter n=482 n=248 n=102 n=103 Bilirubin 7 3 68 55 SGOT (AST) 42 23 53 20 SGPT (ALT) 37 24 50 18 GGT NC NC 28 12 Lipase 17 11 26 19 Amylase NC NC 31 17 NC = Not Collected a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Observed during Clinical Practice: The following events have been identified during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to VIDEX, or a combination of these factors. Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders- anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders - anemia, leukopenia, and thrombocytopenia. Liver - lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 27 of 39 Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS). Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with VIDEX. Adverse events and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults. In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine (see Clinical Studies). Retinal changes and optic neuritis have been reported in pediatric patients. OVERDOSAGE There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage All VIDEX formulations should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen, patients must take at least two of the appropriate strength tablets at each dose to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 28 of 39 provide adequate buffering and prevent gastric acid degradation of didanosine. Because of the need for adequate buffering, the 200-mg strength tablet should only be used as a component of a once-daily regimen. To reduce the risk of gastrointestinal side effects, patients should take no more than four tablets at each dose. Adults: The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see Clinical Studies). The daily dose in adult patients is dependent on weight as outlined in Table 14. Table 14: Adult Dosing Patient Weight VIDEX Tabletsa VIDEX Buffered Powderb Preferred dosing ≥60 kg 200 mg twice daily 250 mg twice daily < 60 kg 125 mg twice daily 167 mg twice daily Dosing for patients whose management requires once-daily frequency ≥ 60 kg 400 mg once daily b < 60 kg 250 mg once daily b a The 200-mg strength tablet should only be used as a component of a once- daily regimen. b Not suitable for once-daily dosing except for patients with renal impairment. See Table 15. Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice daily. Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 29 of 39 Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in patients with confirmed pancreatitis (see WARNINGS). Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should be considered. Renal Impairment: In adult patients with impaired renal function, the dose of VIDEX should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table 15. Table 15: Recommended Dosage of VIDEX in Renal Impairment ≥ 60 kg < 60 kg Creatinine Clearance (mL/min) Tableta (mg) Buffered Powderb (mg) Tableta (mg) Buffered Powderb (mg) ≥60 200 twice dailyc 250 twice daily 125 twice dailyc 167 twice daily 30-59 200 once daily or 100 twice daily 100 twice daily 150 once daily or 75 twice daily 100 twice daily 10-29 150 once daily 167 once daily 100 once daily 100 once daily <10 100 once daily 100 once daily 75 once daily 100 once daily a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose; different strengths of tablets may be combined to yield the recommended dose. b VIDEX Buffered Powder for Oral Solution. c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once- daily frequency of administration. Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the clearance of didanosine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 30 of 39 Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis. Hepatic Impairment: See WARNINGS and PRECAUTIONS. Method of Preparation VIDEX Chewable/Dispersible Buffered Tablets Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable at room temperature, 62° to 73°F (17° to 23°C), for up to one hour. VIDEX Buffered Powder for Oral Solution 1. Open packet carefully and pour contents into a container with approximately 4 ounces of drinking water. Do not mix with fruit juice or other acid-containing liquid. 2. Stir until the powder completely dissolves (approximately 2 to 3 minutes). 3. Drink the entire solution immediately. VIDEX Pediatric Powder for Oral Solution Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a final concentration of 10 mg/mL as follows: 20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 31 of 39 10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution with one part of either Mylanta® Double Strength Liquid, Extra Strength Maalox® Plus Suspension, or Maalox ® TC Suspension for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C). 2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days. HOW SUPPLIED VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on one side and the product strength on the other. The tablets are available in the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with child-resistant closures. The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30 °C). If dispersed in water, the dose may be held for up to 1 hour at ambient temperature. VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single- dose, child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each product strength provides a sweetened, buffered solution of VIDEX. The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in water, the solution may be stored at ambient room temperature for up to 4 hours. VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8- ounce glass bottles containing 2 g or 4 g of VIDEX, respectively. The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any unused portion after 30 days. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 32 of 39 The NDC numbers for the previously described VIDEX products are: Table 16 NDC NO. Packaging Information Product Strength VIDEX Chewable/Dispersible Buffered Tablets 0087-6650-01 60 tablets/bottle 25 mg/tablet 0087-6651-01 60 tablets/bottle 50 mg/tablet 0087-6652-01 60 tablets/bottle 100 mg/tablet 0087-6653-01 60 tablets/bottle 150 mg/tablet 0087-6665-15 60 tablets/bottle 200 mg/tablet VIDEX Buffered Powder for Oral Solution 0087-6614-43 One single-dose foil packet* 100 mg/packet 0087-6615-43 One single-dose foil packet* 167 mg/packet 0087-6616-43 One single-dose foil packet* 250 mg/packet VIDEX Pediatric Powder for Oral Solution 0087-6632-41 One bottle per carton 2 g/bottle 0087-6633-41 One bottle per carton 4 g/bottle * Packaged as 30 packets per carton. US Patent Nos.: 4,861,759 and 5,616,566. HANDLING AND DISPOSAL Spill, Leak, and Disposal Procedure Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge. Clean surface with soap and water as necessary. Containerize larger spills. There is no single preferred method of disposal of containerized waste. Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. Maalox® is a registered trademark of Novartis Consumer Health, Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 33 of 39 Bristol-Myers Squibb Virology A Bristol-Myers Squibb Company Princeton, NJ 08543 USA XXXXXX Revised _____________________ PATIENT INFORMATION Rx only VIDEX® (generic name = didanosine also known as ddI) VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets VIDEX® (didanosine) Buffered Powder for Oral Solution VIDEX® (didanosine) Pediatric Powder for Oral Solution What is VIDEX? VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs to treat children and adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX, you may continue to have HIV-related illnesses, including This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 34 of 39 infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the effects of long-term use of VIDEX. Who should not take VIDEX? Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient, didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. How should I take VIDEX? How should I store it? Your doctor will determine your dose based on your body weight, kidney and liver function, and any side effects that you may have had with other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time you take VIDEX, you must take at least two, but not more than four, tablets. This is because VIDEX tablets contain an antacid to reduce the amount of acid in your stomach. If you have too much acid, the medicine will break down. However, too much antacid may cause stomach problems. —DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in water. Many patients drop the tablets in at least one ounce of water and stir well before swallowing. If you choose to mix the tablets in water, you may add one ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any other kind of juice). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 35 of 39 —Store tablets in a tightly closed container at room temperature away from heat and out of the reach of children and pets. Do NOT store the tablets in a damp place such as a bathroom medicine cabinet or near the kitchen sink. Buffered Powder for Oral Solution: Pour the contents of a packet into a glass with 4 ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink the entire solution right away. Do not mix with fruit juice. Store packets at room temperature before use. Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake the solution well before each use. Store in the refrigerator. Throw away any unused portion after 30 days. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX. Your doctor may also lower your dosage of VIDEX. What should I do if someone takes an overdose of VIDEX? If someone may have taken an overdose of VIDEX, get medical help right away. Contact their doctor or a poison control center. What should I avoid while taking VIDEX? Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Antacids. Since VIDEX contains some of the same ingredients found in antacids, any side effects related to VIDEX’s ingredients may get worse if you also take an antacid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 36 of 39 Medicines at the same time you take your VIDEX dose. Some medicines should not be taken at the same time of day that you take VIDEX. Check with your doctor. Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX. Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX. What are the possible side effects of VIDEX? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX. Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX (including pregnant women). Symptoms that may indicate a liver problem are: • feeling very weak, tired, or uncomfortable, • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 37 of 39 Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you or a child taking VIDEX has continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful. Ask your child’s doctor how to find out if your child is developing peripheral neuropathy. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for you. If so, you might be started at a lower dose. Special note about other medicines. If you take VIDEX along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children may have similar side effects as adults. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 38 of 39 Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. What else should I know about VIDEX? If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains 264.5 mg of sodium. If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of phenylalanine. Inactive Ingredients: Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline cellulose, and magnesium stearate. Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength Maalox Plus or Maalox TC Suspension. This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ApprovletS037.doc (clean copy 27March02) Page 39 of 39 want more information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. Bristol-Myers Squibb Virology A Bristol-Myers Squibb Company Princeton, NJ 08543 USA This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. xxxxxxxx Revised __________________ Based on xxxxx (xx/02) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Jeffrey Murray 4/1/02 04:27:10 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:52.731851	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20154s37lbl.pdf', 'application_number': 20154, 'submission_type': 'SUPPL ', 'submission_number': 37}
12,263	Page 4 of 39 Rx only VIDEX (didanosine) VIDEX (didanosine) Chewable/Dispersible Buffered Tablets VIDEX (didanosine) Buffered Powder for Oral Solution VIDEX (didanosine) Pediatric Powder for Oral Solution (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK. (SEE WARNINGS AND PRECAUTIONS: PREGNANCY.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 of 39 DESCRIPTION VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate. VIDEX Buffered Powder for Oral Solution is supplied for oral administration in single- dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively. Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed- Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine). The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 of 39 MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine- treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 of 39 Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established. CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of VIDEX and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 of 39 Table 1: Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients Pediatric Patientsb Parameter Adult Patientsa n 8 months to 19 years n 2 weeks to 4 months n Oral bioavailability (%) 42 ± 12 6 25 ± 20 46 ND Apparent volume of distributionc (L/m2) 43.70 ± 8.90 6 28 ± 15 49 ND CSF-plasma ratiod 21 ± 0.03%e 5 46% (range 12-85%) 7 ND Systemic clearancec (mL/min/m2) 526 ± 64.7 6 516 ± 184 49 ND Renal clearancef (mL/min/m2) 223 ± 85.0 6 240 ± 90 15 ND Apparent oral clearanceg (mL/min/m2) 1252 ± 154 6 2064 ± 736 48 1353 ± 759 41 Elimination half-lifef (h) 1.5 ± 0.4 6 0.8 ± 0.3 60 1.2 ± 0.3 21 Urinary recovery of didanosinef (%) 18 ± 8 6 18 ± 10 15 ND CSF = cerebrospinal fluid, ND = not determined. a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2. b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-life was 2.0 ± 0.7 h. c Following IV administration. d Following IV administration in adults and IV or oral administration in pediatric patients. e Mean ± SE. f Following oral administration. g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral bioavailability estimate. Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (CMAX) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 of 39 Special Populations Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in adults indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. Table 2: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose Creatinine Clearance (mL/min) Parameter ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 NDa CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 a ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children above 8 months old. For information on controlled clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies and PRECAUTIONS: Pediatric Use. Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age. Gender: The effects of gender on didanosine pharmacokinetics have not been studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 of 39 Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95% confidence interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic interactions were observed. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 of 39 Table 3: Results of Drug Interaction Studies: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑312% ↑232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑113% ↑69% ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8a ↓16% ↓28% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑111% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↔ ↓17% (-27, - 7%)b ↔ ↓13% (-28, 5%)b ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↔ ↓12% methadone, chronic maintenance dose 200 mg single dose 16,10c ↓57% ↓66% tenofovir,d,e 300 mg once daily 1 h after didanosine 250f or 400 mg once daily for 7 days 14 ↑44% (31, 59%)b ↑28% (11, 48%)b No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) loperamide, 4 mg q6h for 1 day 300 mg single dose 12a ↔ ↓23% metoclopramide, 10 mg single dose 300 mg single dose 12a ↔ ↑13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↑14% ↑13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑13% (-1, 27%) ↑17% (-4, 38%) ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓13% (0, 23%) ↓16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↔ ↑17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↔ ↔ ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b 90% CI. c Parallel-group design; entries are subjects receiving combination and control regimens, respectively. d tenofovir disoproxil fumarate. e In a drug interaction study with the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir, the AUC and CMAX of didanosine each increased 48% when VIDEX EC was administered in the fasting state 2 hours before tenofovir with a light meal. The AUC and CMAX of didanosine increased 60% and 64%, respectively, when VIDEX EC was administered together with tenofovir and a light meal. f patients less than 60 kg. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 of 39 Table 4: Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) ciprofloxacin 750 mg q12h for 3 days, 2 h before didanosine 750 mg single dose 200 mg q12h for 3 days buffered placebo tablet 8a 12 ↓26% ↓98% ↓16% ↓93% delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h 12a 12a ↓32% ↑20% ↓53% ↑18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12a ↓21% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↓84% ↓11% ↓82% ↓4% ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↓14% ↓20% nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑12% ↔ No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days 6a ↔ ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↔ ↑17% sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓11% (-17, -4%) ↓12% (-28, 8%) tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↑10% (-9, 34%) ↓22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓10% (-27, 11%) ↓16.5% (-53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b tenofovir disoproxil fumarate. c patients less than 60 kg. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 of 39 INDICATIONS AND USAGE VIDEX in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection (see Clinical Studies). Clinical Studies Combination Therapy START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and increases in CD4 cell counts through 48 weeks. Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks are shown in Figure 1 and Table 5. Figure 1: Treatment Response Through Week 48, AI454-148 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original study medication (except stavudine-zidovudine switches), and have not experienced an AIDS-defining event. 0 20 40 60 80 100 0 8 16 24 32 40 48 Study Week Percent of patients ] < 400 c/mL ] < 50 c/mL VIDEX+stavudine+nelfinavir (n=503) zidovudine+lamivudine+nelfinavir (n=253) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 of 39 Table 5: Outcomes of Randomized Treatment through Week 48, AI454-148 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX/stavudine/nelfinavir lamivudine/zidovudine/nelfinavir Week 48 Status n=503 n=253 Responder a 50* (34) 59 (47) Virologic failureb 36 (57) 32 (48) Death or disease progression <1 (<1) 1 (<1) Discontinued due to adverse events 4 (2) 2 (<1) Discontinued due to other reasonsc 6 (3) 4 (2) Never initiated treatment 4 (4) 2 (2) p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test. a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained it to Week 48. b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48. c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy. Monotherapy The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were similar between the treatment groups. Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death compared with those treated with zidovudine alone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 of 39 Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including VIDEX, was time limited. CONTRAINDICATION VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulations. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX use should be suspended in pediatric This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 16 of 39 patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when administering VIDEX to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.) PRECAUTIONS Frequency of Dosing The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 17 of 39 Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. General Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain the following quantities of phenylalanine: Table 6 All Strengths Phenylalanine per 2-tablet dose 73 mg Phenylalanine per tablet 36.5 mg Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains 1380 mg sodium. Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to patients with significant renal impairment, particularly after prolonged dosing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 18 of 39 Patients with Hepatic Impairment: It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (See Patient Information Leaflet.) Patients should be informed that a serious toxicity of VIDEX used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX may be required if toxicity develops. Patients should be informed that when VIDEX is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when VIDEX is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX toxicities. Patients should be advised that to ensure proper acid neutralization in the stomach they must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the risk of gastrointestinal side effects from excess antacid, patients should take no more than four VIDEX tablets at each dose. VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX. Patients should be advised that This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 19 of 39 VIDEX therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX are unknown at this time. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3 and 4). The clinical recommendations based on the results of these studies are listed in Table 7. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 20 of 39 Table 7: Established Drug Interactions with VIDEX Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ciprofloxacin ↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin. delavirdine ↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine. ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. indinavir ↓ indinavir concentration Administer VIDEX 1 hour after indinavir. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX. tenofovir disoproxil fumarate ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Use with caution and monitor closely for didanosine-associated toxicities (see below). ↑ indicates increase. ↓ indicates decrease. Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX formulations either contain buffers or are mixed with antacids before administration, interactions may be anticipated with drugs whose absorption can be affected by the level of acidity in the stomach and with drugs that have been demonstrated to interact with antacids containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in Table 8. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 21 of 39 Table 8: Predicted Drug Interactions with VIDEX Use with Caution, Risk of Adverse Reactions May Be Increased Drug or Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Antacids containing magnesium or aluminum ↑ side effects associated with antacid components Use caution with VIDEX Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution. Ribavirin ↑ risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Use with caution and monitor closely for didanosine-associated toxicities (see below). Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX Drug Class Effect Clinical Comment Azole antifungals ↓ ketoconazole or itraconazole concentration Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX. Quinolone antibiotics (see also ciprofloxacin in Table 7) ↓ quinolone concentration Consult package insert of the quinolone. Tetracycline antibiotics ↓ antibiotic concentration Consult package insert of the tetracycline. ↑ indicates increase. ↓ indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Tenofovir disoproxil fumarate or ribavirin. Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with either tenofovir (see Tables 3 and 7) or ribavirin (see Table 8). Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir or ribavirin with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS). Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 22 of 39 were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 23 of 39 pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV- infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIDEX. Pediatric Use Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients (see INDICATIONS AND USAGE: Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. Geriatric Use In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 24 of 39 WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). ADVERSE REACTIONS A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When VIDEX is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when VIDEX is used alone. Thus, patients treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with stavudine may also be at increased risk for peripheral neuropathy (see PRECAUTIONS). Adults: Selected clinical adverse events that occurred in adult patients in clinical studies with VIDEX are provided in Tables 9 and 10. Table 9: Selected Clinical Adverse Events from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 Adverse Events VIDEX n=197 zidovudine n=212 VIDEX n=298 zidovudine n=304 Diarrhea 19 15 28 21 Peripheral Neurologic Symptoms/Neuropathy 17 14 20 12 Rash/Pruritus 7 8 9 5 Abdominal Pain 13 8 7 8 Pancreatitis 7 3 6 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 25 of 39 Table 10: Selected Clinical Adverse Events from Combination Studies Percent of Patientsa AI454-148b START 2b Adverse Events VIDEX + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 VIDEX + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 Diarrhea 70 60 45 39 Nausea 28 40 53 67 Headache 21 30 46 37 Peripheral Neurologic Symptoms/Neuropathy 26 6 21 10 Rash 13 16 30 18 Vomiting 12 14 30 35 Pancreatitis (see below) 1 * <1 * a Percentages based on treated subjects. b Median duration of treatment 48 weeks. * This event was not observed in this study arm. Pancreatitis resulting in death was observed in one patient who received VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose. Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 11-13. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 26 of 39 Table 11: Selected Laboratory Abnormalities from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 VIDEX zidovudine VIDEX zidovudine Parameter n=197 n=212 n=298 n=304 SGOT (AST) (>5 x ULN) 9 4 7 6 SGPT (ALT) (>5 x ULN) 9 6 6 6 Alkaline phosphatase (>5 x ULN) 4 1 1 1 Amylase (≥1.4 x ULN) 17 12 15 5 Uric acid (>12 mg/dL) 3 1 2 1 ULN = upper limit of normal. Table 12: Selected Laboratory Abnormalities from Combination Studies (Grades 3-4) Percent of Patientsa AI454-148b START 2b VIDEX + stavudine + nelfinavir zidovudine + lamivudine + nelfinavir VIDEX + stavudine + indinavir zidovudine + lamivudine + indinavir Parameter n=482 n=248 n=102 n=103 Bilirubin (>2.6 x ULN) <1 <1 16 8 SGOT (AST) (>5 x ULN) 3 2 7 7 SGPT (ALT) (>5 x ULN) 3 3 8 5 GGT (>5 x ULN) NC NC 5 2 Lipase (>2 x ULN) 7 2 5 5 Amylase (>2 x ULN) NC NC 8 2 ULN = upper limit of normal. NC=Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 27 of 39 Table 13: Selected Laboratory Abnormalities from Combination Studies (All Grades) Percent of Patientsa I454-148b START 2b Parameter VIDEX + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 VIDEX + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 Bilirubin 7 3 68 55 SGOT (AST) 42 23 53 20 SGPT (ALT) 37 24 50 18 GGT NC NC 28 12 Lipase 17 11 26 19 Amylase NC NC 31 17 NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Observed during Clinical Practice: The following events have been identified during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to VIDEX, or a combination of these factors. Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders- anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders - anemia, leukopenia, and thrombocytopenia. Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 28 of 39 Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with VIDEX. Adverse events and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults. In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND USAGE: Clinical Studies). Retinal changes and optic neuritis have been reported in pediatric patients. OVERDOSAGE There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage All VIDEX formulations should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen, patients must take at least two of the appropriate strength tablets at each dose to provide adequate buffering and prevent gastric acid degradation of didanosine. Because of the need for adequate buffering, the 200-mg strength tablet should only be used as a component of a once-daily regimen. To reduce the risk of gastrointestinal side effects, patients should take no more than four tablets at each dose. Adults: The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 29 of 39 (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult patients is dependent on weight as outlined in Table 14. Table 14: Adult Dosing Patient Weight VIDEX Tabletsa VIDEX Buffered Powderb Preferred dosing ≥60 kg 200 mg twice daily 250 mg twice daily < 60 kg 125 mg twice daily 167 mg twice daily Dosing for patients whose management requires once-daily frequency ≥ 60 kg 400 mg once daily b < 60 kg 250 mg once daily b a The 200-mg strength tablet should only be used as a component of a once-daily regimen. b Not suitable for once-daily dosing except for patients with renal impairment. See Table 15. Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice daily. Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients. Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug Interactions). Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 30 of 39 Renal Impairment: In adult patients with impaired renal function, the dose of VIDEX should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table 15. Table 15: Recommended Dosage of VIDEX in Renal Impairment ≥ 60 kg < 60 kg Creatinine Clearance (mL/min) Tableta (mg) Buffered Powderb (mg) Tableta (mg) Buffered Powderb (mg) ≥60 200 twice dailyc 250 twice daily 125 twice dailyc 167 twice daily 30-59 200 once daily or 100 twice daily 100 twice daily 150 once daily or 75 twice daily 100 twice daily 10-29 150 once daily 167 once daily 100 once daily 100 once daily <10 100 once daily 100 once daily 75 once daily 100 once daily a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose; different strengths of tablets may be combined to yield the recommended dose. b VIDEX Buffered Powder for Oral Solution. c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once- daily frequency of administration. Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the clearance of didanosine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered. Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis. Hepatic Impairment: See WARNINGS and PRECAUTIONS. Method of Preparation VIDEX Chewable/Dispersible Buffered Tablets Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 31 of 39 water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable at room temperature, 62° to 73°F (17° to 23°C), for up to one hour. VIDEX Buffered Powder for Oral Solution 1. Open packet carefully and pour contents into a container with approximately 4 ounces of drinking water. Do not mix with fruit juice or other acid-containing liquid. 2. Stir until the powder completely dissolves (approximately 2 to 3 minutes). 3. Drink the entire solution immediately. VIDEX Pediatric Powder for Oral Solution Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a final concentration of 10 mg/mL as follows: 20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle. 10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution with one part of either Mylanta® Double Strength Liquid, Extra Strength Maalox® Plus Suspension, or Maalox ® TC Suspension for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C). 2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 32 of 39 HOW SUPPLIED VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on one side and the product strength on the other. The tablets are available in the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with child-resistant closures. The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30 °C). If dispersed in water, the dose may be held for up to 1 hour at ambient temperature. VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-dose, child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each product strength provides a sweetened, buffered solution of VIDEX. The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in water, the solution may be stored at ambient room temperature for up to 4 hours. VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8- ounce glass bottles containing 2 g or 4 g of VIDEX, respectively. The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any unused portion after 30 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 33 of 39 The NDC numbers for the previously described VIDEX products are: Table 16 NDC NO. Packaging Information Product Strength VIDEX Chewable/Dispersible Buffered Tablets 0087-6650-01 60 tablets/bottle 25 mg/tablet 0087-6651-01 60 tablets/bottle 50 mg/tablet 0087-6652-01 60 tablets/bottle 100 mg/tablet 0087-6653-01 60 tablets/bottle 150 mg/tablet 0087-6665-15 60 tablets/bottle 200 mg/tablet VIDEX Buffered Powder for Oral Solution 0087-6614-43 One single-dose foil packet* 100 mg/packet 0087-6615-43 One single-dose foil packet* 167 mg/packet 0087-6616-43 One single-dose foil packet* 250 mg/packet VIDEX Pediatric Powder for Oral Solution 0087-6632-41 One bottle per carton 2 g/bottle 0087-6633-41 One bottle per carton 4 g/bottle * Packaged as 30 packets per carton. US Patent Nos.: 4,861,759 and 5,616,566. HANDLING AND DISPOSAL Spill, Leak, and Disposal Procedure Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge. Clean surface with soap and water as necessary. Containerize larger spills. There is no single preferred method of disposal of containerized waste. Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA XXXXXX Revised _____________________ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 34 of 39 PATIENT INFORMATION Rx only VIDEX® (generic name = didanosine also known as ddI) VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets VIDEX® (didanosine) Buffered Powder for Oral Solution VIDEX® (didanosine) Pediatric Powder for Oral Solution What is VIDEX? VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs to treat children and adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the effects of long-term use of VIDEX. Who should not take VIDEX? Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient, didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 35 of 39 How should I take VIDEX? How should I store it? Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with VIDEX or other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time you take VIDEX, you must take at least two, but not more than four, tablets. This is because VIDEX tablets contain an antacid to reduce the amount of acid in your stomach. If you have too much acid, the medicine will break down. However, too much antacid may cause stomach problems. —DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in water. Many patients drop the tablets in at least one ounce of water and stir well before swallowing. If you choose to mix the tablets in water, you may add one ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any other kind of juice). —Store tablets in a tightly closed container at room temperature away from heat and out of the reach of children and pets. Do NOT store the tablets in a damp place such as a bathroom medicine cabinet or near the kitchen sink. Buffered Powder for Oral Solution: Pour the contents of a packet into a glass with 4 ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink the entire solution right away. Do not mix with fruit juice. Store packets at room temperature before use. Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake the solution well before each use. Store in the refrigerator. Throw away any unused portion after 30 days. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX. Your doctor may also lower your dosage of VIDEX. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 36 of 39 What should I do if someone takes an overdose of VIDEX? If someone may have taken an overdose of VIDEX, get medical help right away. Contact their doctor or a poison control center. What should I avoid while taking VIDEX? Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Antacids. Since VIDEX contains some of the same ingredients found in antacids, any side effects related to VIDEX’s ingredients may get worse if you also take an antacid. Medicines at the same time you take your VIDEX dose. Some medicines should not be taken at the same time of day that you take VIDEX. Check with your doctor. Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX. Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX. What are the possible side effects of VIDEX? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 37 of 39 condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX. Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX (including pregnant women). Symptoms that may indicate a liver problem are: • feeling very weak, tired, or uncomfortable, • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you or a child taking VIDEX has continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful. Ask your child’s doctor how to find out if your child is developing peripheral neuropathy. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 38 of 39 get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for you. If so, you might be started at a lower dose. Special note about other medicines. If you take VIDEX along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children may have similar side effects as adults. Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. What else should I know about VIDEX? If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains 264.5 mg of sodium. If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of phenylalanine. Inactive Ingredients: Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline cellulose, and magnesium stearate. Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 39 of 39 Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength Maalox Plus or Maalox TC Suspension. This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. xxxxxxxx Revised __________________ Based on xxxxx (xx/02) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Debra Birnkrant 9/25/02 04:03:13 PM NDA 20-156 NDA 20-155, NDA 20-154 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:53.004644	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20154s40,s41lbl.pdf', 'application_number': 20154, 'submission_type': 'SUPPL ', 'submission_number': 41}
12,264	January 27, 2003 Page 4 of 70 VDXribaJan03FDA.doc (clean) Rx only VIDEX (didanosine) VIDEX (didanosine) Chewable/Dispersible Buffered Tablets VIDEX (didanosine) Buffered Powder for Oral Solution VIDEX (didanosine) Pediatric Powder for Oral Solution (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 5 of 70 VDXribaJan03FDA.doc (clean) DESCRIPTION VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate. VIDEX Buffered Powder for Oral Solution is supplied for oral administration in single-dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively. Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine). The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 6 of 70 VDXribaJan03FDA.doc (clean) MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 7 of 70 VDXribaJan03FDA.doc (clean) Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established. CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of VIDEX and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 8 of 70 VDXribaJan03FDA.doc (clean) Table 1: Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients Pediatric Patientsb Parameter Adult Patientsa n 8 months to 19 years n 2 weeks to 4 months n Oral bioavailability (%) 42 ± 12 6 25 ± 20 46 ND Apparent volume of distributionc (L/m2) 43.70 ± 8.90 6 28 ± 15 49 ND CSF-plasma ratiod 21 ± 0.03%e 5 46% (range 12-85%) 7 ND Systemic clearancec (mL/min/m2) 526 ± 64.7 6 516 ± 184 49 ND Renal clearancef (mL/min/m2) 223 ± 85.0 6 240 ± 90 15 ND Apparent oral clearanceg (mL/min/m2) 1252 ± 154 6 2064 ± 736 48 1353 ± 759 41 Elimination half-lifef (h) 1.5 ± 0.4 6 0.8 ± 0.3 60 1.2 ± 0.3 21 Urinary recovery of didanosinef (%) 18 ± 8 6 18 ± 10 15 ND CSF = cerebrospinal fluid, ND = not determined. a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2. b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-life was 2.0 ± 0.7 h. c Following IV administration. d Following IV administration in adults and IV or oral administration in pediatric patients. e Mean ± SE. f Following oral administration. g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral bioavailability estimate. Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (CMAX) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 9 of 70 VDXribaJan03FDA.doc (clean) Special Populations Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in adults indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. Table 2: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose Creatinine Clearance (mL/min) Parameter ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 ND CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children above 8 months old. For information on controlled clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies and PRECAUTIONS: Pediatric Use. Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age. Gender: The effects of gender on didanosine pharmacokinetics have not been studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 10 of 70 VDXribaJan03FDA.doc (clean) Drug Interactions: Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions). Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95% confidence interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic interactions were observed. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 11 of 70 VDXribaJan03FDA.doc (clean) Table 3: Results of Drug Interaction Studies: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑ 312% ↑ 232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑ 113% ↑ 69% ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8a ↓ 16% ↓ 28% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑ 111% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↔ ↓ 17% (-27, - 7%)b ↔ ↓ 13% (-28, 5%)b ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↔ ↓ 12% methadone, chronic maintenance dose 200 mg single dose 16,10c ↓ 57% ↓ 66% tenofovir,d,e 300 mg once daily 1 h after didanosine 250f or 400 mg once daily for 7 days 14 ↑ 44% (31, 59%)b ↑ 28% (11, 48%)b No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) loperamide, 4 mg q6h for 1 day 300 mg single dose 12a ↔ ↓ 23% metoclopramide, 10 mg single dose 300 mg single dose 12a ↔ ↑ 13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↑ 14% ↑ 13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑ 13% (-1, 27%) ↑ 17% (-4, 38%) ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓ 13% (0, 23%) ↓ 16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↔ ↑ 17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↔ ↔ ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b 90% CI. c Parallel-group design; entries are subjects receiving combination and control regimens, respectively. d tenofovir disoproxil fumarate. e In a drug interaction study with the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir, the AUC and CMAX of didanosine each increased 48% when VIDEX EC was administered in the fasting state 2 hours before tenofovir with a light meal. The AUC and CMAX of didanosine increased 60% and 64%, respectively, when VIDEX EC was administered together with tenofovir and a light meal. f patients less than 60 kg. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 12 of 70 VDXribaJan03FDA.doc (clean) Table 4: Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) ciprofloxacin 750 mg q12h for 3 days, 2 h before didanosine 750 mg single dose 200 mg q12h for 3 days buffered placebo tablet 8a 12 ↓ 26% ↓ 98% ↓ 16% ↓ 93% delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h 12a 12a ↓ 32% ↑ 20% ↓ 53% ↑ 18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12a ↓ 21% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↓ 84% ↓ 11% ↓ 82% ↓ 4% ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↓ 14% ↓ 20% nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑ 12% ↔ No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days 6a ↔ ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓ 16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↔ ↑ 17% sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓ 11% (-17, -4%) ↓ 12% (-28, 8%) tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↑ 10% (-9, 34%) ↓ 22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓ 10% (-27, 11%) ↓ 16.5% (-53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b tenofovir disoproxil fumarate. c patients less than 60 kg. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 13 of 70 VDXribaJan03FDA.doc (clean) INDICATIONS AND USAGE VIDEX in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection (see Clinical Studies). Clinical Studies Combination Therapy START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and increases in CD4 cell counts through 48 weeks. Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks are shown in Figure 1 and Table 5. Figure 1: Treatment Response Through Week 48, AI454-148 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original study medication (except stavudine-zidovudine switches), and have not experienced an AIDS-defining event. 0 20 40 60 80 100 0 8 16 24 32 40 48 Study Week Percent of patients ] < 400 c/mL ] < 50 c/mL VIDEX+stavudine+nelfinavir (n=503) zidovudine+lamivudine+nelfinavir (n=253) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 14 of 70 VDXribaJan03FDA.doc (clean) Table 5: Outcomes of Randomized Treatment through Week 48, AI454-148 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX/stavudine/nelfinavir lamivudine/zidovudine/nelfinavi r Week 48 Status n=503 n=253 Responder a 50* (34) 59 (47) Virologic failureb 36 (57) 32 (48) Death or disease progression <1 (<1) 1 (<1) Discontinued due to adverse events 4 (2) 2 (<1) Discontinued due to other reasonsc 6 (3) 4 (2) Never initiated treatment 4 (4) 2 (2) p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test. a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained it to Week 48. b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48. c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy. Monotherapy The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were similar between the treatment groups. Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death compared with those treated with zidovudine alone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 15 of 70 VDXribaJan03FDA.doc (clean) Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including VIDEX, was time limited. CONTRAINDICATION VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulations. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX use should be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 16 of 70 VDXribaJan03FDA.doc (clean) suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when administering VIDEX to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.) PRECAUTIONS Frequency of Dosing The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 17 of 70 VDXribaJan03FDA.doc (clean) Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. General Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain the following quantities of phenylalanine: Table 6 All Strengths Phenylalanine per 2-tablet dose 73 mg Phenylalanine per tablet 36.5 mg Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains 1380 mg sodium. Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to patients with significant renal impairment, particularly after prolonged dosing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 18 of 70 VDXribaJan03FDA.doc (clean) Patients with Hepatic Impairment: It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (See Patient Information Leaflet.) Patients should be informed that a serious toxicity of VIDEX used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX may be required if toxicity develops. Patients should be informed that when VIDEX is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when VIDEX is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX toxicities. Patients should be advised that to ensure proper acid neutralization in the stomach they must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the risk of gastrointestinal side effects from excess antacid, patients should take no more than four VIDEX tablets at each dose. VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX. Patients should be advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 19 of 70 VDXribaJan03FDA.doc (clean) to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX are unknown at this time. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3 and 4). The clinical recommendations based on the results of these studies are listed in Table 7. Table 7: Established Drug Interactions with VIDEX Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ciprofloxacin ↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin. delavirdine ↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine. ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. indinavir ↓ indinavir concentration Administer VIDEX 1 hour after indinavir. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX. tenofovir disoproxil fumarate ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Use with caution and monitor closely for didanosine-associated toxicities (see below). ↑ indicates increase. ↓ indicates decrease. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 20 of 70 VDXribaJan03FDA.doc (clean) Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX formulations either contain buffers or are mixed with antacids before administration, interactions may be anticipated with drugs whose absorption can be affected by the level of acidity in the stomach and with drugs that have been demonstrated to interact with antacids containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in Table 8. Table 8: Predicted Drug Interactions with VIDEX Use with Caution or Not Recommended, Risk of Adverse Reactions May Be Increased Drug or Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Antacids containing magnesium or aluminum ↑ side effects associated with antacid components Use caution with VIDEX Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution. Ribavirin ↑ risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Coadministration is not recommended (see below). Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX Drug Class Effect Clinical Comment Azole antifungals ↓ ketoconazole or itraconazole concentration Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX. Quinolone antibiotics (see also ciprofloxacin in Table 7) ↓ quinolone concentration Consult package insert of the quinolone. Tetracycline antibiotics ↓ antibiotic concentration Consult package insert of the tetracycline. ↑ indicates increase. ↓ indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Nucleoside/nucleotide analogues Tenofovir disoproxil fumarate. Exposure to didanosine is increased when didanosine is coadministered with tenofovir (see Tables 3 and 7). Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX should be suspended if This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 21 of 70 VDXribaJan03FDA.doc (clean) signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS). Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’- triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 8). Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine and ribavirin is not recommended. Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 22 of 70 VDXribaJan03FDA.doc (clean) slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast- feed if they are receiving VIDEX. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 23 of 70 VDXribaJan03FDA.doc (clean) Pediatric Use Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients (see INDICATIONS AND USAGE: Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. Geriatric Use In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). ADVERSE REACTIONS A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When VIDEX is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when VIDEX is used alone. Thus, patients treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 24 of 70 VDXribaJan03FDA.doc (clean) stavudine may also be at increased risk for peripheral neuropathy (see PRECAUTIONS). Adults: Selected clinical adverse events that occurred in adult patients in clinical studies with VIDEX are provided in Tables 9 and 10. Table 9: Selected Clinical Adverse Events from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 Adverse Events VIDEX n=197 zidovudine n=212 VIDEX n=298 zidovudine n=304 Diarrhea 19 15 28 21 Peripheral Neurologic Symptoms/Neuropathy 17 14 20 12 Rash/Pruritus 7 8 9 5 Abdominal Pain 13 8 7 8 Pancreatitis 7 3 6 2 Table 10: Selected Clinical Adverse Events from Combination Studies Percent of Patientsa AI454-148b START 2b Adverse Events VIDEX + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 VIDEX + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 Diarrhea 70 60 45 39 Nausea 28 40 53 67 Headache 21 30 46 37 Peripheral Neurologic Symptoms/Neuropathy 26 6 21 10 Rash 13 16 30 18 Vomiting 12 14 30 35 Pancreatitis (see below) 1 * <1 * a Percentages based on treated subjects. b Median duration of treatment 48 weeks. * This event was not observed in this study arm. Pancreatitis resulting in death was observed in one patient who received VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 25 of 70 VDXribaJan03FDA.doc (clean) The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose. Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 11-13. Table 11: Selected Laboratory Abnormalities from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 VIDEX zidovudine VIDEX zidovudine Parameter n=197 n=212 n=298 n=304 SGOT (AST) (>5 x ULN) 9 4 7 6 SGPT (ALT) (>5 x ULN) 9 6 6 6 Alkaline phosphatase (>5 x ULN) 4 1 1 1 Amylase (≥1.4 x ULN) 17 12 15 5 Uric acid (>12 mg/dL) 3 1 2 1 ULN = upper limit of normal. Table 12: Selected Laboratory Abnormalities from Combination Studies (Grades 3-4) Percent of Patientsa AI454-148b START 2b VIDEX + stavudine + nelfinavir zidovudine + lamivudine + nelfinavir VIDEX + stavudine + indinavir zidovudine + lamivudine + indinavir Parameter n=482 n=248 n=102 n=103 Bilirubin (>2.6 x ULN) <1 <1 16 8 SGOT (AST) (>5 x ULN) 3 2 7 7 SGPT (ALT) (>5 x ULN) 3 3 8 5 GGT (>5 x ULN) NC NC 5 2 Lipase (>2 x ULN) 7 2 5 5 Amylase (>2 x ULN) NC NC 8 2 ULN = upper limit of normal. NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 26 of 70 VDXribaJan03FDA.doc (clean) Table 13: Selected Laboratory Abnormalities from Combination Studies (All Grades) Percent of Patientsa I454-148b START 2b Parameter VIDEX + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 VIDEX + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 Bilirubin 7 3 68 55 SGOT (AST) 42 23 53 20 SGPT (ALT) 37 24 50 18 GGT NC NC 28 12 Lipase 17 11 26 19 Amylase NC NC 31 17 NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Observed during Clinical Practice: The following events have been identified during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to VIDEX, or a combination of these factors. Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders- anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders - anemia, leukopenia, and thrombocytopenia. Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 27 of 70 VDXribaJan03FDA.doc (clean) Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with VIDEX. Adverse events and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults. In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND USAGE: Clinical Studies). Retinal changes and optic neuritis have been reported in pediatric patients. OVERDOSAGE There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage All VIDEX formulations should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen, patients must take at least two of the appropriate strength tablets at each dose to provide adequate buffering and prevent gastric acid degradation of didanosine. Because of the need for adequate buffering, the 200-mg strength tablet should only be used as a component of a once-daily regimen. To reduce the risk of gastrointestinal side effects, patients should take no more than four tablets at each dose. Adults: The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 28 of 70 VDXribaJan03FDA.doc (clean) of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult patients is dependent on weight as outlined in Table 14. Table 14: Adult Dosing Patient Weight VIDEX Tabletsa VIDEX Buffered Powderb Preferred dosing ≥60 kg 200 mg twice daily 250 mg twice daily < 60 kg 125 mg twice daily 167 mg twice daily Dosing for patients whose management requires once-daily frequency ≥ 60 kg 400 mg once daily b < 60 kg 250 mg once daily b a The 200-mg strength tablet should only be used as a component of a once-daily regimen. b Not suitable for once-daily dosing except for patients with renal impairment. See Table 15. Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice daily. Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients. Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug Interactions). Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should be considered. Renal Impairment: In adult patients with impaired renal function, the dose of VIDEX should be adjusted to compensate for the slower rate of elimination. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 29 of 70 VDXribaJan03FDA.doc (clean) recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table 15. Table 15: Recommended Dosage of VIDEX in Renal Impairment ≥ 60 kg < 60 kg Creatinine Clearance (mL/min) Tableta (mg) Buffered Powderb (mg) Tableta (mg) Buffered Powderb (mg) ≥60 200 twice dailyc 250 twice daily 125 twice dailyc 167 twice daily 30-59 200 once daily or 100 twice daily 100 twice daily 150 once daily or 75 twice daily 100 twice daily 10-29 150 once daily 167 once daily 100 once daily 100 once daily <10 100 once daily 100 once daily 75 once daily 100 once daily a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose; different strengths of tablets may be combined to yield the recommended dose. b VIDEX Buffered Powder for Oral Solution. c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once- daily frequency of administration. Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the clearance of didanosine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered. Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis. Hepatic Impairment: See WARNINGS and PRECAUTIONS. Method of Preparation VIDEX Chewable/Dispersible Buffered Tablets Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 30 of 70 VDXribaJan03FDA.doc (clean) a uniform dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable at room temperature, 62° to 73°F (17° to 23°C), for up to one hour. VIDEX Buffered Powder for Oral Solution 1. Open packet carefully and pour contents into a container with approximately 4 ounces of drinking water. Do not mix with fruit juice or other acid-containing liquid. 2. Stir until the powder completely dissolves (approximately 2 to 3 minutes). 3. Drink the entire solution immediately. VIDEX Pediatric Powder for Oral Solution Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a final concentration of 10 mg/mL as follows: 20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle. 10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution with one part of either Extra Strength Mylanta® Liquid, Extra Strength Maalox® Plus Suspension, or Maalox ® TC Suspension for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C). 2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 31 of 70 VDXribaJan03FDA.doc (clean) HOW SUPPLIED VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on one side and the product strength on the other. The tablets are available in the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with child-resistant closures. The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30 °C). If dispersed in water, the dose may be held for up to 1 hour at ambient temperature. VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single- dose, child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each product strength provides a sweetened, buffered solution of VIDEX. The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in water, the solution may be stored at ambient room temperature for up to 4 hours. VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8- ounce glass bottles containing 2 g or 4 g of VIDEX, respectively. The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any unused portion after 30 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 32 of 70 VDXribaJan03FDA.doc (clean) The NDC numbers for the previously described VIDEX products are: Table 16 NDC NO. Packaging Information Product Strength VIDEX Chewable/Dispersible Buffered Tablets 0087-6650-01 60 tablets/bottle 25 mg/tablet 0087-6651-01 60 tablets/bottle 50 mg/tablet 0087-6652-01 60 tablets/bottle 100 mg/tablet 0087-6653-01 60 tablets/bottle 150 mg/tablet 0087-6665-15 60 tablets/bottle 200 mg/tablet VIDEX Buffered Powder for Oral Solution 0087-6614-43 One single-dose foil packet* 100 mg/packet 0087-6615-43 One single-dose foil packet* 167 mg/packet 0087-6616-43 One single-dose foil packet* 250 mg/packet VIDEX Pediatric Powder for Oral Solution 0087-6632-41 One bottle per carton 2 g/bottle 0087-6633-41 One bottle per carton 4 g/bottle * Packaged as 30 packets per carton. US Patent Nos.: 4,861,759 and 5,616,566. HANDLING AND DISPOSAL Spill, Leak, and Disposal Procedure Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge. Clean surface with soap and water as necessary. Containerize larger spills. There is no single preferred method of disposal of containerized waste. Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA xxxxxx Revised This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 33 of 70 VDXribaJan03FDA.doc (clean) PATIENT INFORMATION Rx only VIDEX® (generic name = didanosine also known as ddI) VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets VIDEX® (didanosine) Buffered Powder for Oral Solution VIDEX® (didanosine) Pediatric Powder for Oral Solution What is VIDEX? VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs to treat children and adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the effects of long-term use of VIDEX. Who should not take VIDEX? Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient, didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 34 of 70 VDXribaJan03FDA.doc (clean) How should I take VIDEX? How should I store it? Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with VIDEX or other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time you take VIDEX, you must take at least two, but not more than four, tablets. This is because VIDEX tablets contain an antacid to reduce the amount of acid in your stomach. If you have too much acid, the medicine will break down. However, too much antacid may cause stomach problems. —DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in water. Many patients drop the tablets in at least one ounce of water and stir well before swallowing. If you choose to mix the tablets in water, you may add one ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any other kind of juice). —Store tablets in a tightly closed container at room temperature away from heat and out of the reach of children and pets. Do NOT store the tablets in a damp place such as a bathroom medicine cabinet or near the kitchen sink. Buffered Powder for Oral Solution: Pour the contents of a packet into a glass with 4 ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink the entire solution right away. Do not mix with fruit juice. Store packets at room temperature before use. Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake the solution well before each use. Store in the refrigerator. Throw away any unused portion after 30 days. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX. Your doctor may also lower your dosage of VIDEX. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 35 of 70 VDXribaJan03FDA.doc (clean) What should I do if someone takes an overdose of VIDEX? If someone may have taken an overdose of VIDEX, get medical help right away. Contact their doctor or a poison control center. What should I avoid while taking VIDEX? Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Antacids. Since VIDEX contains some of the same ingredients found in antacids, any side effects related to VIDEX’s ingredients may get worse if you also take an antacid. Medicines at the same time you take your VIDEX dose. Some medicines should not be taken at the same time of day that you take VIDEX. Check with your doctor. Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX. Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX. What are the possible side effects of VIDEX? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 36 of 70 VDXribaJan03FDA.doc (clean) therapy, let your doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX. Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX (including pregnant women). Symptoms that may indicate a liver problem are: • feeling very weak, tired, or uncomfortable, • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you or a child taking VIDEX has continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful. Ask your child’s doctor how to find out if your child is developing peripheral neuropathy. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 37 of 70 VDXribaJan03FDA.doc (clean) nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for you. If so, you might be started at a lower dose. Special note about other medicines. If you take VIDEX along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children may have similar side effects as adults. Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. What else should I know about VIDEX? If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains 264.5 mg of sodium. If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of phenylalanine. Inactive Ingredients: Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline cellulose, and magnesium stearate. Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 38 of 70 VDXribaJan03FDA.doc (clean) Pediatric Oral Solution: Extra Strength Mylanta Liquid, Extra Strength Maalox Plus or Maalox TC Suspension. This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. xxxxx Revised Based on xxxxx (x/xx) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 39 of 70 VDXECribaJan03FDA.doc (clean) Rx only VIDEX EC (didanosine) VIDEX EC (didanosine) Delayed-Release Capsules Enteric-Coated Beadlets (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT- EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 40 of 70 VDXECribaJan03FDA.doc (clean) DESCRIPTION VIDEX® EC is the brand name for an enteric-coated formulation of didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX EC (didanosine) Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain colloidal silicon dioxide, gelatin, sodium lauryl sulfate, and titanium dioxide. The capsules are imprinted with edible inks. Didanosine is also available as buffered formulations. Please consult the prescribing information for VIDEX (didanosine) buffered formulations and Pediatric Powder for Oral Solution for additional information. The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. In VIDEX EC, an enteric coating is used to protect didanosine from degradation by stomach acid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 41 of 70 VDXECribaJan03FDA.doc (clean) MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'–hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'–triphosphate inhibits the activity of HIV–1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'– triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 42 of 70 VDXECribaJan03FDA.doc (clean) Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established. CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. Table 1: Pharmacokinetic Parameters for Didanosine in Adults Parameter Mean ± SD n Oral bioavailabilitya 42 ± 12% 6 Apparent volume of distributionb 1.08 ± 0.22 L/kg 6 CSF-plasma ratiob 21 ± 0.03%c 5 Systemic clearanceb 13.0 ± 1.6 mL/min/kg 6 Renal clearancea 5.5 ± 2.1 mL/min/kg 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 43 of 70 VDXECribaJan03FDA.doc (clean) Table 1: Pharmacokinetic Parameters for Didanosine in Adults Parameter Mean ± SD n Elimination half-lifea 1.5 ± 0.4 h 6 Urinary recovery of didanosinea 18 ± 8% 6 CSF = cerebrospinal fluid. a following oral administration of a buffered formulation. b following IV administration. c mean ± SE. Comparison of Didanosine Formulations In VIDEX EC, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when the beadlets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid. In healthy volunteers, as well as subjects infected with HIV, the area under the plasma concentration time curve (AUC) is equivalent for didanosine administered as the VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma concentration (CMAX) of didanosine, administered as VIDEX EC, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (TMAX) increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for VIDEX EC. Effect of Food on Absorption of Didanosine In the presence of food, the CMAX and AUC for VIDEX EC were reduced by approximately 46% and 19%, respectively, compared to the fasting state. VIDEX EC should be taken on an empty stomach. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 44 of 70 VDXECribaJan03FDA.doc (clean) Special Populations Renal Insufficiency It is recommended that the VIDEX EC (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies using a buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. Table 2: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered Formulation Creatinine Clearance (mL/min) Parameter ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 NDa CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 a ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. Pediatric Patients The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in pediatric patients. Geriatric Patients Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see PRECAUTIONS: Geriatric Use). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 45 of 70 VDXECribaJan03FDA.doc (clean) Gender The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions (See also PRECAUTIONS: Drug Interactions.) Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions). VIDEX EC Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval (CI) when available, following coadministration of VIDEX EC with a variety of drugs. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 46 of 70 VDXECribaJan03FDA.doc (clean) Table 3: Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Valuesa Drug Didanosine Dosage n AUC of Didanosine (90% CI) CMAX of Didanosine (90% CI) tenofovir,b 300 mg once daily with a light mealc 400 mg single dose fasting 2 h before tenofovir 26 ↑ 48% (31, 67%) ↑ 48% (25, 76%) tenofovir,b 300 mg once daily with a light mealc 400 mg single dose together with tenofovir and a light meal 25 ↑ 60% (44, 79%) ↑ 64% (41, 89%) ↑ indicates increase. a All studies conducted in healthy volunteers. b tenofovir disoproxil fumarate. c 373 kcalories, 8.2 grams fat. Table 4: Results of Drug Interaction Studies with VIDEX EC: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Valuesa Drug Didanosine Dosage n AUC of Coadministered Drug CMAX of Coadministered Drug ciprofloxacin, 750 mg single dose 400 mg single dose 16 ↔ ↔ indinavir, 800 mg single dose 400 mg single dose 23 ↔ ↔ ketoconazole, 200 mg single dose 400 mg single dose 21 ↔ ↔ tenofovir,b 300 mg once daily with a light mealc 400 mg single dose fasting 2 h before tenofovir 25 ↔ ↔ tenofovir,b 300 mg once daily with a light mealc 400 mg single dose together with tenofovir and a light meal 25 ↔ ↔ ↔ indicates no change, or mean increase or decrease of <10%. a All studies conducted in healthy volunteers. b tenofovir disoproxil fumarate. c 373 kcalories, 8.2 grams fat. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 47 of 70 VDXECribaJan03FDA.doc (clean) Didanosine Buffered Formulations Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% CI when available, following coadministration of buffered formulations of didanosine with a variety of drugs. Except as noted in table footnotes, the results of these studies may be expected to apply to VIDEX EC. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 48 of 70 VDXECribaJan03FDA.doc (clean) Table 5: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑ 312% ↑ 232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑ 113% ↑ 69% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑ 111% NA methadone, chronic maintenance dose 200 mg single dose 16,10a ↓ 57% ↓ 66% tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↑ 44% (31, 59%)d ↑ 28% (11, 48%)d No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8e ↓ 16% ↓ 28% indinavir, 800 mg single dose simultaneous 200 mg single dose 16 ↔ ↔ 1 h before didanosine 200 mg single dose 16 ↓ 17% (-27, -7%)d ↓ 13% (-28, 5%)d ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12e ↔ ↓12% loperamide, 4 mg q6h for 1 day 300 mg single dose 12e ↔ ↓23% metoclopramide, 10 mg single dose 300 mg single dose 12e ↔ ↑13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12e ↑14% ↑13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑ 13% (-1, 27%) ↑ 17% (-4, 38%) ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓ 13% (0, 23%) ↓ 16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8e ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8e ↔ ↑ 17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6e ↔ ↔ ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a Parallel-group design; entries are subjects receiving combination and control regimens, respectively. b tenofovir disoproxil fumarate. c patients less than 60 kg. d 90% Cl. e HIV-infected patients. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 49 of 70 VDXECribaJan03FDA.doc (clean) Table 6: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days 6a ↔ ↔ delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h 12a 12a ↓ 32%b ↑ 20% ↓ 53%b ↑ 18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12a ↓21% NA nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑12% ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↔ ↑17% sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓ 11% (-17, -4%) ↓ 12% (-28, 8%) tenofovir,c 300 mg once daily 1 h after didanosine 250d or 400 mg once daily for 7 days 14 ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↑ 10% (-9, 34%) ↓ 22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓ 10% (-27, 11%) ↓ 16.5% (-53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b This result is probably related to the buffer and is not expected to occur with VIDEX EC. c tenofovir disoproxil fumarate. d patients less than 60 kg. NA Not available. INDICATIONS AND USAGE VIDEX EC (didanosine) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in adults. (See Clinical Studies.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 50 of 70 VDXECribaJan03FDA.doc (clean) Clinical Studies Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV RNA <400 and <50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 7, respectively. Figure 1 Treatment Response Through Week 48, AI454-152 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL and do not meet any criteria for treatment failure (eg, virologic failure or discontinuation for any reason). 0 20 40 60 80 100 0 12 24 36 48 Study Week Percent of Patients ] < 400 c/mL ] < 50 c/mL VIDEX EC+stavudine+nelfinavir, n=258 zidovudine/lamivudine+nelfinavir, n=253 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 51 of 70 VDXECribaJan03FDA.doc (clean) Table 7: Outcomes of Randomized Treatment Through Week 48, AI454-152 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX EC + stavudine + zidovudine/lamivudinea + nelfinavir nelfinavir Outcome n=258 n=253 Responderb,c 55% (33%) 56% (33%) Virologic failured 22% (45%) 21% (43%) Death or discontinued due to disease progression 1% (1%) 2% (2%) Discontinued due to adverse event 6% (6%) 7% (7%) Discontinued due to other reasonse 16% (16%) 15% (16%) a Zidovudine/lamivudine combination tablet. b Corresponds to rates at Week 48 in Figure 1. c Subjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated, and other reasons. CONTRAINDICATION VIDEX EC (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any component of the formulation. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT- EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 52 of 70 VDXECribaJan03FDA.doc (clean) VIDEX EC IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX EC therapy is recommended. In patients with risk factors for pancreatitis, VIDEX EC should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when administering VIDEX EC to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX EC should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients receiving VIDEX EC. (See ADVERSE REACTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 53 of 70 VDXECribaJan03FDA.doc (clean) PRECAUTIONS Dosing VIDEX EC should be administered once daily on an empty stomach. Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. General Patients with Renal Impairment Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). Patients with Hepatic Impairment It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 54 of 70 VDXECribaJan03FDA.doc (clean) Hyperuricemia Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (See Patient Information Leaflet.) Patients should be informed that a serious toxicity of didanosine, used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX EC (didanosine). Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX EC may be required if toxicity develops. Patients should be informed that when didanosine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when didanosine is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX EC toxicities. VIDEX EC is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX EC. Patients should be advised that VIDEX EC therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX EC are unknown at this time. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 55 of 70 VDXECribaJan03FDA.doc (clean) Interactions (Tables 3-6). The clinical recommendations based on the results of these studies are listed in Table 8. Table 8: Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX EC Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. tenofovir disoproxil fumarate ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Use with caution and monitor closely for didanosine-associated toxicities (see below). ↑ indicates increase. ↓ indicates decrease. Coadministration of VIDEX EC with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Predicted drug interactions with VIDEX EC are listed in Table 9. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 56 of 70 VDXECribaJan03FDA.doc (clean) Table 9: Predicted Drug Interactions with VIDEX EC Drug or Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Ribavirin ↑ risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Coadministration is not recommended (see below). ↑ indicates increase. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Nucleoside/nucleotide analogues Tenofovir disoproxil fumarate. Exposure to didanosine is increased when didanosine is coadministered with tenofovir (see Tables 3, 5, and 8). Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX EC should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX EC should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS). Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’- triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 9). Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine and ribavirin is not recommended. Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 57 of 70 VDXECribaJan03FDA.doc (clean) low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 58 of 70 VDXECribaJan03FDA.doc (clean) stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast- feed if they are receiving VIDEX EC (didanosine). Pediatric Use The safety and efficacy of VIDEX EC in pediatric patients have not been established. Please consult the complete prescribing information for VIDEX (didanosine) buffered formulations and Pediatric Powder for Oral Solution for dosage and administration of didanosine to pediatric patients. Geriatric Use In an Expanded Access Program using a buffered formulation of didanosine for the treatment of advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical studies of didanosine, including those for VIDEX EC, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 59 of 70 VDXECribaJan03FDA.doc (clean) adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). ADVERSE REACTIONS A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with VIDEX EC in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and hepatotoxicity (see WARNINGS). Patients treated with VIDEX EC in combination with stavudine may also be at increased risk for peripheral neuropathy (see PRECAUTIONS). Selected clinical adverse events that occurred in a study of VIDEX EC in combination with other antiretroviral agents are provided in Table 10. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 60 of 70 VDXECribaJan03FDA.doc (clean) Table 10: Selected Clinical Adverse Events, Study AI454-152a Percent of Patientsb VIDEX EC + stavudine + nelfinavir zidovudine/ lamivudinec + nelfinavir Adverse Events n=258 n=253 Diarrhea 57 58 Peripheral Neurologic Symptoms/Neuropathy 25 11 Nausea 24 36 Headache 22 17 Rash 14 12 Vomiting 14 19 Pancreatitis (see below) <1 * a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group. b Percentages based on treated patients. c Zidovudine/lamivudine combination tablet. * This event was not observed in this study arm. In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. Selected laboratory abnormalities that occurred in a study of VIDEX EC in combination with other antiretroviral agents are shown in Table 11. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 61 of 70 VDXECribaJan03FDA.doc (clean) Table 11: Selected Laboratory Abnormalities, Study AI454-152a Percent of Patientsb VIDEX EC + stavudine + nelfinavir n=258 zidovudine/lamivudinec + nelfinavir n=253 Parameter Grades 3-4d All Grades Grades 3-4d All Grades SGOT (AST) 5 46 5 19 SGPT (ALT) 6 44 5 22 Lipase 5 23 2 13 Bilirubin <1 9 <1 3 a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group. b Percentages based on treated patients. c Zidovudine/lamivudine combination tablet. d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN = upper limit of normal). Observed During Clinical Practice The following events have been identified during postapproval use of didanosine buffered formulations. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors. Body as a Whole – abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders- anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders - anemia, leukopenia, and thrombocytopenia. Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 62 of 70 VDXECribaJan03FDA.doc (clean) Metabolic Disorders - diabetes mellitus, elevated serum alkaline phosphatase level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS). OVERDOSAGE There is no known antidote for didanosine overdosage. In phase 1 studies, in which buffered formulations of didanosine were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage Adults VIDEX EC (didanosine) should be administered on an empty stomach. VIDEX EC Delayed-Release Capsules should be swallowed intact. The recommended daily dose is dependent on body weight and is administered as one capsule given on a once-daily schedule as outlined in Table 12. Table 12: Dosing of VIDEX EC Delayed-Release Capsules Patient Weight Dosage ≥60 kg 400 mg once daily <60 kg 250 mg once daily This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 63 of 70 VDXECribaJan03FDA.doc (clean) Pediatric Patients VIDEX EC has not been studied in pediatric patients. Please consult the complete prescribing information for VIDEX (didanosine) buffered formulations and Pediatric Powder for Oral Solution for dosage and administration of didanosine to pediatric patients. Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX EC use should be discontinued in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug Interactions). Based on data with buffered didanosine formulations, patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX EC after resolution of the symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after resumption of VIDEX EC, permanent discontinuation of VIDEX EC should be considered. Renal Impairment Dosing recommendations for VIDEX EC and VIDEX buffered formulations are different for patients with renal impairment. Please consult the complete prescribing information on administration of VIDEX (didanosine) buffered formulations to patients with renal impairment. In adult patients with impaired renal function, the dose of VIDEX EC should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX EC in adult patients with renal insufficiency are presented in Table 13. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 64 of 70 VDXECribaJan03FDA.doc (clean) Table 13: Recommended Dosage of VIDEX EC in Renal Impairment by Body Weighta Dosage Creatinine Clearance (mL/min) ≥60 kg <60 kg ≥60 400 once daily 250 once daily 30-59 200 once daily 125 once daily 10-29 125 once daily 125 once daily <10 125 once daily b a Based on studies using a buffered formulation of didanosine. b Not suitable for use in patients <60 kg with CLcr <10 mL/min. An alternate formulation of didanosine should be used. Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to administer a supplemental dose of didanosine following hemodialysis. Hepatic Impairment (See WARNINGS and PRECAUTIONS.) HOW SUPPLIED VIDEX® EC (didanosine) Delayed-Release Capsules are white, opaque capsules that are packaged in bottles with child-resistant closures as described in Table 14. Table 14: VIDEX EC Delayed-Release Capsules 125 mg capsule imprinted with BMS 125 mg 6671 in Tan NDC No. 0087-6671-17 30 capsules/bottle 200 mg capsule imprinted with BMS 200 mg 6672 in Green NDC No. 0087-6672-17 30 capsules/bottle 250 mg capsule imprinted with BMS 250 mg 6673 in Blue NDC No. 0087-6673-17 30 capsules/bottle 400 mg capsule imprinted with BMS 400 mg 6674 in Red NDC No. 0087-6674-17 30 capsules/bottle This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 65 of 70 VDXECribaJan03FDA.doc (clean) The capsules should be stored in tightly closed containers at 25° C (77° F). Excursions between 15° and 30° C (59° and 86° F) are permitted [see USP Controlled Room Temperature]. HANDLING AND DISPOSAL Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. US Patent Nos: 4,861,759 and 5,616,566 (didanosine). Patent also Pending (didanosine capsules). Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA xxxxxx Revised This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 66 of 70 VDXECribaJan03FDA.doc (clean) PATIENT INFORMATION Rx only VIDEX® EC (generic name = didanosine also known as ddI) VIDEX® EC (didanosine) Delayed-Release Capsules Enteric-Coated Beadlets What is VIDEX EC? VIDEX EC (pronounced VY dex ee see) is a prescription medicine used in combination with other drugs to treat adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX EC belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX EC helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX EC will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX EC, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX EC does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the antiviral response of long-term use of VIDEX EC. In VIDEX EC, an enteric coating is used to protect the medicine while it is in your stomach since stomach acids can break it down. The enteric coating dissolves when the medicine reaches your small intestine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 67 of 70 VDXECribaJan03FDA.doc (clean) Who should not take VIDEX EC? Do not take VIDEX EC if you are allergic to any of its ingredients, including its active ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. Because it has only been studied in adults, VIDEX EC is not recommended for children. How should I take VIDEX EC? How should I store it? VIDEX EC should only be taken once daily. Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with VIDEX EC or other medicines. Take VIDEX EC on an empty stomach. Do not take VIDEX EC with food. Swallow the capsule whole; do not open it. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Store capsules in a tightly closed container at room temperature away from heat and out of the reach of children and pets. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX EC. Your doctor may also lower your dosage of VIDEX EC. What should I do if someone takes an overdose of VIDEX EC? If someone may have taken an overdose of VIDEX EC, get medical help right away. Contact their doctor or a poison control center. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 68 of 70 VDXECribaJan03FDA.doc (clean) What should I avoid while taking VIDEX EC? Alcohol. Do not drink alcohol while taking VIDEX EC since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX EC. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Pregnancy. It is not known if VIDEX EC can harm a human fetus. Also, pregnant women have experienced serious side effects when taking didanosine (the active ingredient in VIDEX EC) in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX EC should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX EC. Nursing. Studies have shown didanosine (the active ingredient in VIDEX EC) is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX EC. What are the possible side effects of VIDEX EC? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you develop stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX EC therapy, let your doctor know if you have ever had pancreatitis. This condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX EC. Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX EC (including pregnant women). Symptoms that may indicate a liver problem are: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 69 of 70 VDXECribaJan03FDA.doc (clean) • feeling very weak, tired, or uncomfortable, • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX EC and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX EC. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX EC may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you have continuing numbness, tingling, or pain in the feet or hands. Before starting VIDEX EC therapy, let your doctor know if you have ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX EC. After stopping VIDEX EC, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX EC is right for you. If so, you might be started at a lower dose. Special note about other medicines. If you take VIDEX EC along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX EC in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda January 27, 2003 Page 70 of 70 VDXECribaJan03FDA.doc (clean) Other side effects: The most common side effects in adults taking VIDEX EC in combination with other HIV drugs included diarrhea, nausea, headache, vomiting, and rash. Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. Inactive Ingredients: Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, talc, colloidal silicon dioxide, gelatin, sodium lauryl sulfate, and titanium dioxide. This medicine was prescribed for your particular condition. Do not use VIDEX EC for another condition or give it to others. Keep VIDEX EC and all medicines out of the reach of children. Throw away VIDEX EC when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX EC. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about VIDEX EC, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. xxxxxx Revised Based on xxxxxx (x/xx) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:53.416756	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20154slr042,20156slr033,20155slr032,21183slr007videx_lbl.pdf', 'application_number': 20154, 'submission_type': 'SUPPL ', 'submission_number': 42}
12,265	NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 3 Rx only VIDEX EC (didanosine) VIDEX EC (didanosine) Delayed-Release Capsules Enteric-Coated Beadlets (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT- EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 4 DESCRIPTION VIDEX® EC is the brand name for an enteric-coated formulation of didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX EC (didanosine) Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain colloidal silicon dioxide, gelatin, sodium lauryl sulfate, and titanium dioxide. The capsules are imprinted with edible inks. Didanosine is also available as buffered formulations. Please consult the prescribing information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution for additional information. The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. In VIDEX EC, an enteric coating is used to protect didanosine from degradation by stomach acid. MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'–hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 5 5'-triphosphate. Dideoxyadenosine 5'–triphosphate inhibits the activity of HIV–1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'–triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine- treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 6 CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. Pharmacokinetic Parameters for Didanosine in Adults Parameter Mean ± SD n Oral bioavailabilitya 42 ± 12% 6 Apparent volume of distributionb 1.08 ± 0.22 L/kg 6 CSF-plasma ratiob 21 ± 0.03%c 5 Systemic clearanceb 13.0 ± 1.6 mL/min/kg 6 Renal clearancea 5.5 ± 2.1 mL/min/kg 6 Elimination half-lifea 1.5 ± 0.4 h 6 Urinary recovery of didanosinea 18 ± 8% 6 CSF = cerebrospinal fluid. a following oral administration of a buffered formulation. b following IV administration. c mean ± SE. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 7 Comparison of Didanosine Formulations In VIDEX EC, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when the beadlets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid. In healthy volunteers, as well as subjects infected with HIV, the area under the plasma concentration time curve (AUC) is equivalent for didanosine administered as the VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma concentration (CMAX) of didanosine, administered as VIDEX EC, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (TMAX) increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for VIDEX EC. Effect of Food on Absorption of Didanosine In the presence of food, the CMAX and AUC for VIDEX EC were reduced by approximately 46% and 19%, respectively, compared to the fasting state. VIDEX EC should be taken on an empty stomach. Special Populations Renal Insufficiency It is recommended that the VIDEX EC (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies using a buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 8 Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered Formulation Creatinine Clearance (mL/min) Parameter ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 ND CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. Pediatric Patients The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in pediatric patients. Geriatric Patients Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see PRECAUTIONS: Geriatric Use). Gender The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions (See also PRECAUTIONS: Drug Interactions.) Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 9 VIDEX EC Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval (CI) when available, following coadministration of VIDEX EC with a variety of drugs. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 10 Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Valuesa Drug Didanosine Dosage n AUC of Didanosine (90% CI) CMAX of Didanosine (90% CI) tenofovir,b 300 mg once daily with a light mealc 400 mg single dose fasting 2 h before tenofovir 2 6 ↑ 48% (31, 67%) ↑ 48% (25, 76%) tenofovir,b 300 mg once daily with a light mealc 400 mg single dose with tenofovir and a light meal 2 5 ↑ 60% (44, 79%) ↑ 64% (41, 89%) tenofovir,b 300 mg once daily with a light mealc 200 mg single dose with tenofovir and a light meal 3 3 ↑ 16% (6, 27%)d ↓ 12% (−25, 3%)d 250 mg single dose with tenofovir and a light meal 3 3 ↔ (−13, 5%)e ↓ 20% (−32, −7%)e 325 mg single dose with tenofovir and a light meal 3 3 ↑ 13% (3, 24%)e ↓ 11% (−24, 4%)e ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min. b tenofovir disoproxil fumarate. c 373 kcalories, 8.2 grams fat. d Compared with VIDEX EC 250 mg administered alone under fasting conditions. e Compared with VIDEX EC 400 mg administered alone under fasting conditions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 11 Results of Drug Interaction Studies with VIDEX EC: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Valuesa Drug Didanosine Dosage n AUC of Coadministered Drug CMAX of Coadministered Drug ciprofloxacin, 750 mg single dose 400 mg single dose 1 6 ↔ ↔ indinavir, 800 mg single dose 400 mg single dose 2 3 ↔ ↔ ketoconazole, 200 mg single dose 400 mg single dose 2 1 ↔ ↔ tenofovir,b 300 mg once daily with a light mealc 400 mg single dose fasting 2 h before tenofovir 2 5 ↔ ↔ tenofovir,b 300 mg once daily with a light mealc 400 mg single dose with tenofovir and a light meal 2 5 ↔ ↔ ↔ indicates no change, or mean increase or decrease of <10%. a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min. b tenofovir disoproxil fumarate. c 373 kcalories, 8.2 grams fat. Didanosine Buffered Formulations Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% CI when available, following coadministration of buffered formulations of didanosine with a variety of drugs. Except as noted in table footnotes, the results of these studies may be expected to apply to VIDEX EC. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION (for tenofovir). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 12 Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑ 312% ↑ 232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 1 4 ↑ 113% ↑ 69% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 1 2 ↑ 111% NA methadone, chronic maintenance dose 200 mg single dose 1 6 , 1 0 a ↓ 57% ↓ 66% tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 1 4 ↑ 44% (31, 59%)d ↑ 28% (11, 48%)d No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8 e ↓ 16% ↓ 28% indinavir, 800 mg single dose simultaneous 200 mg single dose 1 6 ↔ ↔ 1 h before didanosine 200 mg single dose 1 6 ↓ 17% (-27, -7%)d ↓ 13% (-28, 5%)d ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 1 2 e ↔ ↓12% loperamide, 4 mg q6h for 1 day 300 mg single dose 1 2 e ↔ ↓23% metoclopramide, 10 mg single dose 300 mg single dose 1 2 e ↔ ↑13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 1 2 e ↑14% ↑13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 1 1 ↑ 13% (-1, 27%) ↑ 17% (-4, 38%) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 13 Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 1 2 ↓ 13% (0, 23%) ↓ 16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 1 0 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8 e ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8 e ↔ ↑ 17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6 e ↔ ↔ ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a Parallel-group design; entries are subjects receiving combination and control regimens, respectively. b tenofovir disoproxil fumarate. c patients <60 kg with creatinine clearance >60 mL/min. d 90% Cl. e HIV-infected patients. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 14 Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values No Clinically Significant Interaction Observed Drug Didanosine Dosage AUC of Coadminister ed Drug (95% CI) CMAX of Coadminister ed Drug (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days ↔ ↔ delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h ↓ 32%b ↑ 20% ↓ 53%b ↑ 18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h ↓21% NA nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose ↑12% ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose ↓16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days ↔ ↑17% sulfamethoxazole, 1000 mg single dose 200 mg single dose ↓ 11% (-17, - 4%) ↓ 12% (-28, 8%) tenofovir,c 300 mg once daily 1 h after didanosine 250d or 400 mg once daily for 7 days ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose ↑ 10% (-9, 34%) ↓ 22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days ↓ 10% (-27, 11%) ↓ 16.5% (-53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b This result is probably related to the buffer and is not expected to occur with VIDEX EC. c tenofovir disoproxil fumarate. d patients <60 kg with creatinine clearance >60 mL/min. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 15 INDICATIONS AND USAGE VIDEX EC (didanosine) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in adults. (See Clinical Studies.) Clinical Studies Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV RNA <400 and <50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 7, respectively. Figure 1 Treatment Response Through Week 48, AI454-152 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 16 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL and do not meet any criteria for treatment failure (eg, virologic failure or discontinuation for any reason). 0 20 40 60 80 100 0 12 24 36 48 Study Week Percent of Patients ] < 400 c/mL ] < 50 c/mL VIDEX EC+stavudine+nelfinavir, n=258 zidovudine/lamivudine+nelfinavir, n=253 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 17 Outcomes of Randomized Treatment Through Week 48, AI454-152 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX EC + stavudine + zidovudine/lamivudinea + nelfinavir nelfinavir Outcome n=258 n=253 Responderb,c 55% (33%) 56% (33%) Virologic failured 22% (45%) 21% (43%) Death or discontinued due to disease progression 1% (1%) 2% (2%) Discontinued due to adverse event 6% (6%) 7% (7%) Discontinued due to other reasonse 16% (16%) 15% (16%) a Zidovudine/lamivudine combination tablet. b Corresponds to rates at Week 48 in Figure 1. c Subjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated, and other reasons. CONTRAINDICATION VIDEX EC (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any component of the formulation. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX EC SHOULD BE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 18 SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX EC IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX EC therapy is recommended. In patients with risk factors for pancreatitis, VIDEX EC should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when administering VIDEX EC to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX EC should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients receiving VIDEX EC. (See ADVERSE REACTIONS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 19 PRECAUTIONS Dosing VIDEX EC should be administered once daily on an empty stomach. Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. General Patients with Renal Impairment Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). Patients with Hepatic Impairment It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 20 Hyperuricemia Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (See Patient Information Leaflet.) Patients should be informed that a serious toxicity of didanosine, used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX EC (didanosine). Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX EC may be required if toxicity develops. Patients should be informed that when didanosine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when didanosine is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX EC toxicities. VIDEX EC is not a cure for HIV infection, and patients may continue to develop HIV- associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX EC. Patients should be advised that VIDEX EC therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX EC are unknown at this time. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 21 Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3-6). The clinical recommendations based on the results of these studies are listed in Table 8. Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX EC Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily taken together with tenofovir and a light meal (≤400 kcalories and ≤20% fat) or in the fasted state is recommended. Patients should be monitored for didanosine-associated toxicities (see below). ↑ indicates increase. ↓ indicates decrease. Coadministration of VIDEX EC with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Predicted drug interactions with VIDEX EC are listed in Table 9. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 22 Predicted Drug Interactions with VIDEX EC Drug or Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Ribavirin ↑ risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Coadministration is not recommended (see below). ↑ indicates increase. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Nucleoside/nucleotide analogues Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered with tenofovir (see Tables 3, 5, and 8). Increased exposure may cause or worsen didanosine- related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX EC should be undertaken with caution, and patients should be monitored closely for didanosine- related toxicities. VIDEX EC should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS). Administration of reduced doses of VIDEX EC with tenofovir and a light meal resulted in didanosine exposures (AUC) similar to the recommended doses of VIDEX EC given alone in the fasted state (see Table 3). Therefore, when administered with tenofovir, a dose reduction of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended, and both drugs may be taken together with a light meal (≤400 kcalories, ≤20% fat) or in the fasted state (see DOSAGE AND ADMINISTRATION). Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 9). Fatal hepatic failure, as This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 23 well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine and ribavirin is not recommended. Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 24 its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800- 258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIDEX EC (didanosine). Pediatric Use The safety and efficacy of VIDEX EC in pediatric patients have not been established. Please consult the complete prescribing information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution for dosage and administration of didanosine to pediatric patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 25 Geriatric Use In an Expanded Access Program using a buffered formulation of didanosine for the treatment of advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical studies of didanosine, including those for VIDEX EC, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). ADVERSE REACTIONS A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with VIDEX EC in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and hepatotoxicity (see WARNINGS). Patients treated with VIDEX EC in combination with stavudine may also be at increased risk for peripheral neuropathy (see PRECAUTIONS). Selected clinical adverse events that occurred in a study of VIDEX EC in combination with other antiretroviral agents are provided in Table 10. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 26 Selected Clinical Adverse Events, Study AI454-152a Percent of Patientsb VIDEX EC + stavudine + nelfinavir zidovudine/ lamivudinec + nelfinavir Adverse Events n=258 n=253 Diarrhea 57 58 Peripheral Neurologic Symptoms/Neuro pathy 25 11 Nausea 24 36 Headache 22 17 Rash 14 12 Vomiting 14 19 Pancreatitis (see below) <1 * a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group. b Percentages based on treated patients. c Zidovudine/lamivudine combination tablet. * This event was not observed in this study arm. In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. Selected laboratory abnormalities that occurred in a study of VIDEX EC in combination with other antiretroviral agents are shown in Table 11. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 27 Selected Laboratory Abnormalities, Study AI454-152a Percent of Patientsb VIDEX EC + stavudine + nelfinavir n=258 zidovudine/lamivudinec + nelfinavir n=253 Parameter Grades 3- 4d All Grades Grades 3- 4d All Grades SGOT (AST) 5 46 5 19 SGPT (ALT) 6 44 5 22 Lipase 5 23 2 13 Bilirubin <1 9 <1 3 a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group. b Percentages based on treated patients. c Zidovudine/lamivudine combination tablet. d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN = upper limit of normal). Observed During Clinical Practice The following events have been identified during postapproval use of didanosine buffered formulations. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors. Body as a Whole – abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders- anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders - anemia, leukopenia, and thrombocytopenia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 28 Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. Metabolic Disorders - diabetes mellitus, elevated serum alkaline phosphatase level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS). OVERDOSAGE There is no known antidote for didanosine overdosage. In phase 1 studies, in which buffered formulations of didanosine were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage Adults VIDEX EC (didanosine) should be administered on an empty stomach. VIDEX EC Delayed-Release Capsules should be swallowed intact. The recommended daily dose is dependent on body weight and is administered as one capsule given on a once-daily schedule as outlined in Table 12. Dosing of VIDEX EC Delayed-Release Capsules Patient Weight Dosage ≥60 kg 400 mg once daily <60 kg 250 mg once daily This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 29 Pediatric Patients VIDEX EC has not been studied in pediatric patients. Please consult the complete prescribing information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution for dosage and administration of didanosine to pediatric patients. Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX EC use should be discontinued in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug Interactions). Based on data with buffered didanosine formulations, patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX EC after resolution of the symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after resumption of VIDEX EC, permanent discontinuation of VIDEX EC should be considered. Concomitant Therapy Tenofovir disoproxil fumarate. A dose reduction of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily taken together with tenofovir and a light meal (≤400 kcalories, ≤20% fat) or in the fasted state is recommended. The appropriate dose of VIDEX EC coadministered with tenofovir in patients with creatinine clearance <60 mL/min has not been established. (See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions.) Renal Impairment Dosing recommendations for VIDEX EC and VIDEX buffered formulations are different for patients with renal impairment. Please consult the complete prescribing information on administration of VIDEX (didanosine) buffered formulations to patients with renal impairment. In adult patients with impaired renal function, the dose of VIDEX EC should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX EC in adult patients with renal insufficiency are presented in Table 13. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 30 Recommended Dosage of VIDEX EC in Renal Impairment by Body Weighta Dosage Creatinine Clearance (mL/min) ≥60 kg <60 kg ≥60 400 once daily 250 once daily 30-59 200 once daily 125 once daily 10-29 125 once daily 125 once daily <10 125 once daily b a Based on studies using a buffered formulation of didanosine. b Not suitable for use in patients <60 kg with CLcr <10 mL/min. An alternate formulation of didanosine should be used. Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to administer a supplemental dose of didanosine following hemodialysis. Hepatic Impairment (See WARNINGS and PRECAUTIONS.) HOW SUPPLIED VIDEX® EC (didanosine) Delayed-Release Capsules are white, opaque capsules that are packaged in bottles with child-resistant closures as described in Table 14. VIDEX EC Delayed-Release Capsules 125 mg capsule imprinted with BMS 125 mg 6671 in Tan NDC No. 0087-6671-17 30 capsules/bottle 200 mg capsule imprinted with BMS 200 mg 6672 in Green NDC No. 0087-6672-17 30 capsules/bottle 250 mg capsule imprinted with BMS 250 mg 6673 in Blue NDC No. 0087-6673-17 30 capsules/bottle 400 mg capsule imprinted with BMS 400 mg 6674 in Red NDC No. 0087-6674-17 30 capsules/bottle This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 31 The capsules should be stored in tightly closed containers at 25° C (77° F). Excursions between 15° and 30° C (59° and 86° F) are permitted [see USP Controlled Room Temperature]. HANDLING AND DISPOSAL Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. US Patent Nos: 4,861,759, 5,254,539, and 5,880,106 (didanosine). Patent also Pending (didanosine capsules). Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA XXXXX-XX XXXXXXXXX Revised ____________ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 32 PATIENT INFORMATION Rx only VIDEX® EC (generic name = didanosine also known as ddI) VIDEX® EC (didanosine) Delayed-Release Capsules Enteric-Coated Beadlets What is VIDEX EC? VIDEX EC (pronounced VY dex ee see) is a prescription medicine used in combination with other drugs to treat adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX EC belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX EC helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX EC will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX EC, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX EC does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the antiviral response of long-term use of VIDEX EC. In VIDEX EC, an enteric coating is used to protect the medicine while it is in your stomach since stomach acids can break it down. The enteric coating dissolves when the medicine reaches your small intestine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 33 Who should not take VIDEX EC? Do not take VIDEX EC if you are allergic to any of its ingredients, including its active ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. Because it has only been studied in adults, VIDEX EC is not recommended for children. How should I take VIDEX EC? How should I store it? VIDEX EC should only be taken once daily. Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with VIDEX EC or other medicines. Take VIDEX EC on an empty stomach. Do not take VIDEX EC with food. Swallow the capsule whole; do not open it. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Store capsules in a tightly closed container at room temperature away from heat and out of the reach of children and pets. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX EC. Your doctor may also lower your dosage of VIDEX EC. What should I do if someone takes an overdose of VIDEX EC? If someone may have taken an overdose of VIDEX EC, get medical help right away. Contact their doctor or a poison control center. What should I avoid while taking VIDEX EC? Alcohol. Do not drink alcohol while taking VIDEX EC since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 34 Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX EC or may increase the possibility or severity of side effects. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Pregnancy. It is not known if VIDEX EC can harm a human fetus. Also, pregnant women have experienced serious side effects when taking didanosine (the active ingredient in VIDEX EC) in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX EC should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX EC. Nursing. Studies have shown didanosine (the active ingredient in VIDEX EC) is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX EC. What are the possible side effects of VIDEX EC? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you develop stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX EC therapy, let your doctor know if you have ever had pancreatitis. This condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX EC. Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX EC (including pregnant women). Symptoms that may indicate a liver problem are: • feeling very weak, tired, or uncomfortable, • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 35 Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX EC and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX EC. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX EC may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you have continuing numbness, tingling, or pain in the feet or hands. Before starting VIDEX EC therapy, let your doctor know if you have ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX EC. After stopping VIDEX EC, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX EC is right for you. If so, you might be started at a lower dose. Special note about other medicines. If you take VIDEX EC along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX EC in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. Other side effects: The most common side effects in adults taking VIDEX EC in combination with other HIV drugs included diarrhea, nausea, headache, vomiting, and rash. Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 36 Inactive Ingredients: Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, talc, colloidal silicon dioxide, gelatin, sodium lauryl sulfate, and titanium dioxide. This medicine was prescribed for your particular condition. Do not use VIDEX EC for another condition or give it to others. Keep VIDEX EC and all medicines out of the reach of children. Throw away VIDEX EC when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX EC. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about VIDEX EC, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. XXXXX-XX XXXXXXXXX Revised _____________________ Based on package insert dated ______________________ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 37 Rx only VIDEX (didanosine) VIDEX (didanosine) Chewable/Dispersible Buffered Tablets VIDEX (didanosine) Pediatric Powder for Oral Solution (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY). DESCRIPTION VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 38 Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate. VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively. Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine). The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 39 In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine- treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established. CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 40 the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of VIDEX and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 41 Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients Pediatric Patientsb Parameter Adult Patients a 8 months to 19 years 2 weeks to 4 months Oral bioavailability (%) 42 ± 12 25 ± 20 ND Apparent volume of distributionc (L/m2) 43.70 ± 8.90 28 ± 15 ND CSF-plasma ratiod 21 ± 0.03%e 46% (range 12- 85%) ND Systemic clearancec (mL/min/m2) 526 ± 64.7 516 ± 184 ND Renal clearancef (mL/min/m2) 223 ± 85.0 240 ± 90 ND Apparent oral clearanceg (mL/min/m2) 1252 ± 154 2064 ± 736 1353 ± 759 Elimination half- lifef (h) 1.5 ± 0.4 0.8 ± 0.3 1.2 ± 0.3 Urinary recovery of didanosinef (%) 18 ± 8 18 ± 10 ND CSF = cerebrospinal fluid, ND = not determined. a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2. b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-life was 2.0 ± 0.7 h. c Following IV administration. d Following IV administration in adults and IV or oral administration in pediatric patients. e Mean ± SE. f Following oral administration. g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral bioavailability estimate. Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (CMAX) and area under the plasma concentration time curve (AUC) were decreased by This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 42 approximately 55% when VIDEX tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.) Special Populations Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in adults indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose Creatinine Clearance (mL/min) Paramet er ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min ) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 ND CL/F (mL/min ) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min ) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV- exposed and -infected pediatric patients from birth to 19 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 43 above 8 months old. For information on controlled clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies and PRECAUTIONS: Pediatric Use. Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age. Gender: The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions: Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions). Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95% confidence interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic interactions were observed. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION (for tenofovir). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 44 Results of Drug Interaction Studies with VIDEX: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑ 312% ↑ 232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑ 113% ↑ 69% ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8a ↓ 16% ↓ 28% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑ 111% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↔ ↓ 17% (-27, - 7%)b ↔ ↓ 13% (-28, 5%)b ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12 a ↔ ↓ 12% methadone, chronic maintenance dose 200 mg single dose 16, 10 c ↓ 57% ↓ 66% tenofovir,d,e 300 mg once daily 1 h after didanosine 250f or 400 mg once daily for 7 days 14 ↑ 44% (31, 59%)b ↑ 28% (11, 48%)b No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) loperamide, 4 mg q6h for 1 day 300 mg single dose 12 a ↔ ↓ 23% metoclopramide, 10 mg single dose 300 mg single dose 12 a ↔ ↑ 13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12 a ↑ 14% ↑ 13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑ 13% (-1, 27%) ↑ 17% (-4, 38%) ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓ 13% (0, 23%) ↓ 16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↔ ↑ 17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↔ ↔ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 45 Results of Drug Interaction Studies with VIDEX: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b 90% CI. c Parallel-group design; entries are subjects receiving combination and control regimens, respectively. d tenofovir disoproxil fumarate. e For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir, see the complete prescribing information for VIDEX EC. f patients <60 kg with creatinine clearance >60 mL/min. NA Not available. Results of Drug Interaction Studies with VIDEX: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Coadministe red Drug (95% CI) CMAX of Coadministe red Drug (95% CI) ciprofloxacin 750 mg q12h for 3 days, 2 h before didanosine 750 mg single dose 200 mg q12h for 3 days buffered placebo tablet 8 a 1 2 ↓ 26% ↓ 98% ↓ 16% ↓ 93% delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h 1 2 a 1 2 a ↓ 32% ↑ 20% ↓ 53% ↑ 18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 1 2 a ↓ 21% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 1 6 1 6 ↓ 84% ↓ 11% ↓ 82% ↓ 4% ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 1 2 a ↓ 14% ↓ 20% nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 1 0 a ↑ 12% ↔ No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Coadministe red Drug CMAX of Coadministe red Drug This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 46 Results of Drug Interaction Studies with VIDEX: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values (95% CI) (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days 6 a ↔ ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 1 2 a ↓ 16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 1 2 ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 1 0 a ↔ ↑ 17% sulfamethoxazole, 1000 mg single dose 200 mg single dose 8 a ↓ 11% (-17, -4%) ↓ 12% (-28, 8%) tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 1 4 ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8 a ↑ 10% (-9, 34%) ↓ 22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6 a ↓ 10% (-27, 11%) ↓ 16.5% (- 53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b tenofovir disoproxil fumarate. c patients <60 kg with creatinine clearance >60 mL/min. NA Not available. INDICATIONS AND USAGE VIDEX in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection (see Clinical Studies). Clinical Studies Combination Therapy START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and increases in CD4 cell counts through 48 weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 47 Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks are shown in Figure 1 and Table 5. re 1: Treatment Response Through Week 48, AI454-148 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original study medication (except stavudine-zidovudine switches), and have not experienced an AIDS-defining event. 0 20 40 60 80 100 0 8 16 24 32 40 48 Study Week Percent of patients ] < 400 c/mL ] < 50 c/mL VIDEX+stavudine+nelfinavir (n=503) zidovudine+lamivudine+nelfinavir (n=253) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 48 Outcomes of Randomized Treatment through Week 48, AI454-148 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX/stavudine/nelfina vir lamivudine/zidovudine/ne lfinavir Week 48 Status n=503 n=253 Responder a 50* (34) 59 (47) Virologic failureb 36 (57) 32 (48) Death or disease progression <1 (<1) 1 (<1) Discontinued due to adverse events 4 (2) 2 (<1) Discontinued due to other reasonsc 6 (3) 4 (2) Never initiated treatment 4 (4) 2 (2) p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test. a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained it to Week 48. b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48. c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy. Monotherapy The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more than one year. In treatment- naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were similar between the treatment groups. Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death compared with those treated with zidovudine alone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 49 Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including VIDEX, was time limited. CONTRAINDICATION VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulations. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX use should be suspended in pediatric patients with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 50 signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when administering VIDEX to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.) PRECAUTIONS Frequency of Dosing The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 51 Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. General Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain the following quantities of phenylalanine: All Strengths Phenylalanine per 2-tablet dose 73 mg Phenylalanine per tablet 36.5 mg Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to patients with significant renal impairment, particularly after prolonged dosing. Patients with Hepatic Impairment: It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 52 Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (See Patient Information Leaflet.) Patients should be informed that a serious toxicity of VIDEX used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX may be required if toxicity develops. Patients should be informed that when VIDEX is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when VIDEX is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX toxicities. Patients should be advised that to ensure proper acid neutralization in the stomach they must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the risk of gastrointestinal side effects from excess antacid, patients should take no more than four VIDEX tablets at each dose. VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX. Patients should be advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX are unknown at this time. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 53 Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3 and 4). The clinical recommendations based on the results of these studies are listed in Table 7. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 54 Established Drug Interactions with VIDEX Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ciprofloxaci n ↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin. delavirdine ↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine. ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. indinavir ↓ indinavir concentration Administer VIDEX 1 hour after indinavir. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX. tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities (see below). ↑ indicates increase. ↓ indicates decrease. Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX formulations either contain buffers or are mixed with antacids before administration, interactions This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 55 may be anticipated with drugs whose absorption can be affected by the level of acidity in the stomach and with drugs that have been demonstrated to interact with antacids containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in Table 8. Predicted Drug Interactions with VIDEX Use with Caution or Not Recommended, Risk of Adverse Reactions May Be Increased Drug or Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Antacids containing magnesium or aluminum ↑ side effects associated with antacid components Use caution with VIDEX Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution. Ribavirin ↑ risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Coadministration is not recommended (see below). Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX Drug Class Effect Clinical Comment Azole antifungals ↓ ketoconazole or itraconazole concentration Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX. Quinolone antibiotics (see also ciprofloxacin in Table 7) ↓ quinolone concentration Consult package insert of the quinolone. Tetracycline antibiotics ↓ antibiotic concentration Consult package insert of the tetracycline. ↑ indicates increase. ↓ indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Nucleoside/nucleotide analogues Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered with tenofovir (see Table 3). Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 56 hyperlactatemia, or lactic acidosis develop (see WARNINGS). A dose reduction of VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty stomach, at least 30 minutes before food or 2 hours after food (see DOSAGE AND ADMINISTRATION). (The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC.) Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 8). Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine and ribavirin is not recommended. Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 57 mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800- 258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 58 the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIDEX. Pediatric Use Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients (see INDICATIONS AND USAGE: Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. Geriatric Use In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). ADVERSE REACTIONS A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When VIDEX is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when VIDEX is used alone. Thus, patients treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 59 at increased risk for pancreatitis, which may be fatal, and hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with stavudine may also be at increased risk for peripheral neuropathy (see PRECAUTIONS). Adults: Selected clinical adverse events that occurred in adult patients in clinical studies with VIDEX are provided in Tables 9 and 10. Selected Clinical Adverse Events from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 Adverse Events VID EX n=19 7 zidovudin e n=212 VIDEX n=298 zidovudin e n=304 Diarrhea 19 15 28 21 Peripheral Neurologic Symptoms/Neuropat hy 17 14 20 12 Rash/Pruritus 7 8 9 5 Abdominal Pain 13 8 7 8 Pancreatitis 7 3 6 2 Selected Clinical Adverse Events from Combination Studies Percent of Patientsa AI454-148b START 2b Adverse Events VIDE X + stavu dine + nelfin avir n=48 2 zidovudin e + lamivudin e + nelfinavir n=248 VIDEX + stavudin e + indinavi r n=102 zidovudin e + lamivudin e + indinavir n=103 Diarrhea 70 60 45 39 Nausea 28 40 53 67 Headache 21 30 46 37 Peripheral Neurologic Symptoms/Neuropat hy 26 6 21 10 Rash 13 16 30 18 Vomiting 12 14 30 35 Pancreatitis (see below) 1 * <1 * a Percentages based on treated subjects. b Median duration of treatment 48 weeks. * This event was not observed in this study arm. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 60 Pancreatitis resulting in death was observed in one patient who received VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose. Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 11- 13. Selected Laboratory Abnormalities from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 VIDEX zidovudine VIDEX zidovudin e Parameter n=197 n=212 n=298 n=304 SGOT (AST) (>5 x ULN) 9 4 7 6 SGPT (ALT) (>5 x ULN) 9 6 6 6 Alkaline phosphatase (>5 x ULN) 4 1 1 1 Amylase (≥1.4 x ULN) 17 12 15 5 Uric acid (>12 mg/dL) 3 1 2 1 ULN = upper limit of normal. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 61 Selected Laboratory Abnormalities from Combination Studies (Grades 3-4) Percent of Patientsa AI454-148b START 2b VIDEX + stavudine + nelfinavir zidovudine + lamivudine + nelfinavir VIDEX + stavudine + indinavir zidovudine + lamivudine + indinavir Parameter n=482 n=248 n=102 n=103 Bilirubin (>2.6 x ULN) <1 <1 16 8 SGOT (AST) (>5 x ULN) 3 2 7 7 SGPT (ALT) (>5 x ULN) 3 3 8 5 GGT (>5 x ULN) NC NC 5 2 Lipase (>2 x ULN) 7 2 5 5 Amylase (>2 x ULN) NC NC 8 2 ULN = upper limit of normal. NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Selected Laboratory Abnormalities from Combination Studies (All Grades) Percent of Patientsa AI454-148b START 2b Parameter VIDE X + stavud ine + nelfina vir n=482 zidovudin e + lamivudin e + nelfinavir n=248 VIDE X + stavudi ne + indinav ir n=102 zidovudin e + lamivudin e + indinavir n=103 Bilirubin 7 3 68 55 SGOT (AST) 42 23 53 20 SGPT (ALT) 37 24 50 18 GGT NC NC 28 12 Lipase 17 11 26 19 Amylase NC NC 31 17 NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Observed during Clinical Practice: The following events have been identified during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 62 population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to VIDEX, or a combination of these factors. Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders- anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders - anemia, leukopenia, and thrombocytopenia. Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS). Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with VIDEX. Adverse events and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults. In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND USAGE: Clinical Studies). Retinal changes and optic neuritis have been reported in pediatric patients. OVERDOSAGE There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 63 Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage All VIDEX formulations should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen, patients must take at least two of the appropriate strength tablets at each dose to provide adequate buffering and prevent gastric acid degradation of didanosine. Because of the need for adequate buffering, the 200-mg strength tablet should only be used as a component of a once-daily regimen. To reduce the risk of gastrointestinal side effects, patients should take no more than four tablets at each dose. Adults: The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult patients is dependent on weight as outlined in Table 14. Adult Dosinga Recommended VIDEX Dose by Patient Weight ≥60 kg <60 kg Preferred dosing 200 mg twice daily 125 mg twice daily Dosing for patients whose management requires once- daily frequency 400 mg once daily 250 mg once daily a The 200-mg strength tablet should only be used as a component of a once-daily regimen. Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice daily. Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 64 Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug Interactions). Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should be considered. Concomitant Therapy: Tenofovir disoproxil fumarate. A dose reduction of VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). The appropriate dose of VIDEX coadministered with tenofovir in patients with creatinine clearance <60 mL/min has not been established. [See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions; see the complete prescribing information for VIDEX EC (enteric-coated formulation of didanosine) for results of drug interaction studies of tenofovir with reduced doses of the enteric-coated formulation of didanosine.] Renal Impairment: In adult patients with impaired renal function, the dose of VIDEX should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table 15. Recommended Dosage of VIDEX in Renal Impairmenta Recommended VIDEX Dose by Patient Weight Creatinine Clearance (mL/min) ≥60 kg <60 kg ≥60 200 mg twice dailyb 125 twice dailyb 30-59 200 mg once daily or 100 mg twice daily 150 mg once daily or 75 mg twice daily 10-29 150 mg once daily 100 mg once daily <10 100 mg once daily 75 mg once daily a Two VIDEX Chewable/Dispersible Buffered tablets must be taken with each dose; different strengths of tablets may be combined to yield the recommended dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 65 Recommended Dosage of VIDEX in Renal Impairmenta b 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once-daily frequency of administration. Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the clearance of didanosine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered. Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis. Hepatic Impairment: See WARNINGS and PRECAUTIONS. Method of Preparation VIDEX Chewable/Dispersible Buffered Tablets Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable at room temperature, 62° to 73°F (17° to 23°C), for up to one hour. VIDEX Pediatric Powder for Oral Solution Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a final concentration of 10 mg/mL as follows: 20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 66 10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution with one part of either Maximum Strength Mylanta® Liquid or Extra Strength Maalox® Plus Suspension for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C). 2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days. HOW SUPPLIED VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on one side and the product strength on the other. The tablets are available in the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with child-resistant closures. The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30° C). If dispersed in water, the dose may be held for up to 1 hour at ambient temperature. VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-ounce glass bottles containing 2 g or 4 g of VIDEX, respectively. The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any unused portion after 30 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 67 The NDC numbers for the previously described VIDEX products are: NDC NO. Packaging Information Product Strength VIDEX Chewable/Dispersible Buffered Tablets 0087-6650-01 60 tablets/bottle 25 mg/tablet 0087-6651-01 60 tablets/bottle 50 mg/tablet 0087-6652-01 60 tablets/bottle 100 mg/tablet 0087-6653-01 60 tablets/bottle 150 mg/tablet 0087-6665-15 60 tablets/bottle 200 mg/tablet VIDEX Pediatric Powder for Oral Solution 0087-6632-41 One bottle per carton 2 g/bottle 0087-6633-41 One bottle per carton 4 g/bottle US Patent Nos.: 4,861,759, 5,254,539, and 5,880,106. HANDLING AND DISPOSAL Spill, Leak, and Disposal Procedure Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge. Clean surface with soap and water as necessary. Containerize larger spills. There is no single preferred method of disposal of containerized waste. Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA XXXXX-XX XXXXXXXXX Revised _________________ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 68 Patient Information Rx only VIDEX® (generic name = didanosine also known as ddI) VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets VIDEX® (didanosine) Pediatric Powder for Oral Solution What is VIDEX? VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs to treat children and adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the effects of long-term use of VIDEX. Who should not take VIDEX? Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient, didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 69 How should I take VIDEX? How should I store it? Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with VIDEX or other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time you take VIDEX, you must take at least two, but not more than four, tablets. This is because VIDEX tablets contain an antacid to reduce the amount of acid in your stomach. If you have too much acid, the medicine will break down. However, too much antacid may cause stomach problems. —DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in water. Many patients drop the tablets in at least one ounce of water and stir well before swallowing. If you choose to mix the tablets in water, you may add one ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any other kind of juice). —Store tablets in a tightly closed container at room temperature away from heat and out of the reach of children and pets. Do NOT store the tablets in a damp place such as a bathroom medicine cabinet or near the kitchen sink. Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake the solution well before each use. Store in the refrigerator. Throw away any unused portion after 30 days. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX. Your doctor may also lower your dosage of VIDEX. What should I do if someone takes an overdose of VIDEX? If someone may have taken an overdose of VIDEX, get medical help right away. Contact their doctor or a poison control center. What should I avoid while taking VIDEX? Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 70 Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX or may increase the possibility or severity of side effects. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Antacids. Since VIDEX contains some of the same ingredients found in antacids, any side effects related to VIDEX’s ingredients may get worse if you also take an antacid. Medicines at the same time you take your VIDEX dose. Some medicines should not be taken at the same time of day that you take VIDEX. Check with your doctor. Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX. Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX. What are the possible side effects of VIDEX? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX. Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX (including pregnant women). Symptoms that may indicate a liver problem are: • feeling very weak, tired, or uncomfortable, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 71 • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you or a child taking VIDEX has continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful. Ask your child’s doctor how to find out if your child is developing peripheral neuropathy. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for you. If so, you might be started at a lower dose. Special note about other medicines. If you take VIDEX along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 72 Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children may have similar side effects as adults. Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. What else should I know about VIDEX? If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of phenylalanine. Inactive Ingredients: Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline cellulose, and magnesium stearate. Pediatric Oral Solution: Maximum Strength Mylanta Liquid or Extra Strength Maalox Plus. This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-044 NDA 20-155/S-034 NDA 20-156/S-035 NDA 21-183/S-010 Page 73 This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. Revised _________________ XXXXX-XX Based on package insert dated _____________ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:53.492821	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20154slr044,20155slr034,20156slr035,21183s010_videx_lbl.pdf', 'application_number': 20154, 'submission_type': 'SUPPL ', 'submission_number': 44}
12,267	NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 5 of 72 Rx only VIDEX® (didanosine) VIDEX® (didanosine) Pediatric Powder for Oral Solution (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY, REPRODUCTION, AND FERTILITY). DESCRIPTION VIDEX® (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 6 of 72 VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively. Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed-Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine). The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 7 of 72 In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 8 of 72 CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of VIDEX and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 9 of 72 Table 1: Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients Pediatric Patientsb Parameter Adult Patientsa n 8 months to 19 years n 2 weeks to 4 months n Oral bioavailability (%) 42 ± 12 6 25 ± 20 46 ND Apparent volume of distributionc (L/m2) 43.70 ± 8.90 6 28 ± 15 49 ND CSF-plasma ratiod 21 ± 0.03%e 5 46% (range 12-85%) 7 ND Systemic clearancec (mL/min/m2) 526 ± 64.7 6 516 ± 184 49 ND Renal clearancef (mL/min/m2) 223 ± 85.0 6 240 ± 90 15 ND Apparent oral clearanceg (mL/min/m2) 1252 ± 154 6 2064 ± 736 48 1353 ± 759 41 Elimination half-lifef (h) 1.5 ± 0.4 6 0.8 ± 0.3 60 1.2 ± 0.3 21 Urinary recovery of didanosinef (%) 18 ± 8 6 18 ± 10 15 ND CSF = cerebrospinal fluid, ND = not determined. a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2. b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-life was 2.0 ± 0.7 h. c Following IV administration. d Following IV administration in adults and IV or oral administration in pediatric patients. e Mean ± SE. f Following oral administration. g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral bioavailability estimate. Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (CMAX) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 10 of 72 Special Populations Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in adults indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. Table 2: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose Creatinine Clearance (mL/min) Parameter ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 ND CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children above 8 months old. For information on controlled clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies and PRECAUTIONS: Pediatric Use. Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 11 of 72 Gender: The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions: Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions). Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95% confidence interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic interactions were observed. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION (for tenofovir). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 12 of 72 Table 3: Results of Drug Interaction Studies with VIDEX: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑ 312% ↑ 232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑ 113% ↑ 69% ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8a ↓ 16% ↓ 28% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑ 111% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↔ ↓ 17% (-27, - 7%)b ↔ ↓ 13% (-28, 5%)b ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↔ ↓ 12% methadone, chronic maintenance dose 200 mg single dose 16, 10c ↓ 57% ↓ 66% tenofovir,d,e 300 mg once daily 1 h after didanosine 250f or 400 mg once daily for 7 days 14 ↑ 44% (31, 59%)b ↑ 28% (11, 48%)b No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) loperamide, 4 mg q6h for 1 day 300 mg single dose 12a ↔ ↓ 23% metoclopramide, 10 mg single dose 300 mg single dose 12a ↔ ↑ 13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↑ 14% ↑ 13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑ 13% (-1, 27%) ↑ 17% (-4, 38%) ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓ 13% (0, 23%) ↓ 16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↔ ↑ 17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↔ ↔ ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b 90% CI. c Parallel-group design; entries are subjects receiving combination and control regimens, respectively. d tenofovir disoproxil fumarate. e For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir, see the complete prescribing information for VIDEX EC. f patients <60 kg with creatinine clearance ≥60 mL/min. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 13 of 72 Table 4: Results of Drug Interaction Studies with VIDEX: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) ciprofloxacin 750 mg q12h for 3 days, 2 h before didanosine 750 mg single dose 200 mg q12h for 3 days buffered placebo tablet 8a 12 ↓ 26% ↓ 98% ↓ 16% ↓ 93% delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h 12a 12a ↓ 32% ↑ 20% ↓ 53% ↑ 18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12a ↓ 21% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↓ 84% ↓ 11% ↓ 82% ↓ 4% ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↓ 14% ↓ 20% nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑ 12% ↔ No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days 6a ↔ ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓ 16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↔ ↑ 17% sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓ 11% (-17, -4%) ↓ 12% (-28, 8%) tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↑ 10% (-9, 34%) ↓ 22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓ 10% (-27, 11%) ↓ 16.5% (-53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b tenofovir disoproxil fumarate. c patients <60 kg with creatinine clearance ≥60 mL/min. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 14 of 72 INDICATIONS AND USAGE VIDEX (didanosine) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection (see Clinical Studies). Clinical Studies Combination Therapy START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and increases in CD4 cell counts through 48 weeks. Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks are shown in Figure 1 and Table 5. Figure 1: Treatment Response Through Week 48, AI454-148 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original study medication (except stavudine-zidovudine switches), and have not experienced an AIDS-defining event. 0 20 40 60 80 100 0 8 16 24 32 40 48 Study Week Percent of patients ] < 400 c/mL ] < 50 c/mL VIDEX+stavudine+nelfinavir (n=503) zidovudine+lamivudine+nelfinavir (n=253) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 15 of 72 Table 5: Outcomes of Randomized Treatment through Week 48, AI454-148 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX/stavudine/nelfinavir lamivudine/zidovudine/nelfinavir Week 48 Status n=503 n=253 Responder a 50* (34) 59 (47) Virologic failureb 36 (57) 32 (48) Death or disease progression <1 (<1) 1 (<1) Discontinued due to adverse events 4 (2) 2 (<1) Discontinued due to other reasonsc 6 (3) 4 (2) Never initiated treatment 4 (4) 2 (2) p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test. a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained it to Week 48. b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48. c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy. Monotherapy The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG 116B/117, conducted 1989- 1991) patients with symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were similar between the treatment groups. Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine (120 mg/m2q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death compared with those treated with zidovudine alone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 16 of 72 Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including VIDEX, was time limited. CONTRAINDICATION VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulations. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 17 of 72 didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX (didanosine) use should be suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy, Reproduction, and Fertility). Particular caution should be exercised when administering VIDEX to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.) 4. Hepatic Impairment and Toxicity It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. The safety and efficacy of VIDEX have not been established in HIV- infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 18 of 72 potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. PRECAUTIONS Frequency of Dosing The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 19 of 72 The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIDEX. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. General Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (see Patient Information Leaflet) Patients should be informed that a serious toxicity of VIDEX used alone and in combination regimens is pancreatitis, which may be fatal. Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 20 of 72 with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX may be required if toxicity develops. Patients should be informed that when VIDEX is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when VIDEX is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX toxicities. VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX. Patients should be advised that VIDEX therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX are unknown at this time. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3 and 4). The clinical recommendations based on the results of these studies are listed in Table 6. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 21 of 72 Table 6: Established Drug Interactions with VIDEX Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ciprofloxacin ↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin. delavirdine ↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine. ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. indinavir ↓ indinavir concentration Administer VIDEX 1 hour after indinavir. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX. tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities and clinical response (see below). ↑ indicates increase. ↓ indicates decrease. Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX is mixed with an antacid before administration, interactions may be anticipated with drugs whose absorption can be affected by the level of acidity in the stomach and with drugs that have been demonstrated to interact with antacids containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in Table 7. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 22 of 72 Table 7: Predicted Drug Interactions with VIDEX Use with Caution or Not Recommended, Risk of Adverse Reactions May Be Increased Drug or Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Antacids containing magnesium or aluminum ↑ side effects associated with antacid components Use caution with VIDEX Pediatric Powder for Oral Solution. Ribavirin ↑ risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Coadministration is not recommended (see below). Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX Drug Class Effect Clinical Comment Azole antifungals ↓ ketoconazole or itraconazole concentration Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX. Quinolone antibiotics (see also ciprofloxacin in Table 6) ↓ quinolone concentration Consult package insert of the quinolone. Tetracycline antibiotics ↓ antibiotic concentration Consult package insert of the tetracycline. ↑ indicates increase. ↓ indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Nucleoside/nucleotide analogues Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered with tenofovir (see Table 3). Increased exposure may cause or worsen didanosine- related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS). A dose reduction of VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty stomach, at least 30 minutes before food or 2 hours after food This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 23 of 72 (see DOSAGE AND ADMINISTRATION). (The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC.) Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5’- triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 7). Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine and ribavirin is not recommended. Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/-mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 24 of 72 Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 25 of 72 were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast- feed if they are receiving VIDEX. Pediatric Use Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients (see INDICATIONS AND USAGE: Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. Geriatric Use In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). ADVERSE REACTIONS A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 26 of 72 AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When VIDEX is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when VIDEX is used alone. Thus, patients treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy (see WARNINGS and PRECAUTIONS). Adults: Selected clinical adverse events that occurred in adult patients in clinical studies with VIDEX are provided in Tables 8 and 9. Table 8: Selected Clinical Adverse Events from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 Adverse Events VIDEX n=197 zidovudine n=212 VIDEX n=298 zidovudine n=304 Diarrhea 19 15 28 21 Peripheral Neurologic Symptoms/Neuropathy 17 14 20 12 Rash/Pruritus 7 8 9 5 Abdominal Pain 13 8 7 8 Pancreatitis 7 3 6 2 Table 9: Selected Clinical Adverse Events from Combination Studies Percent of Patientsa AI454-148b START 2b Adverse Events VIDEX + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 VIDEX + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 Diarrhea 70 60 45 39 Nausea 28 40 53 67 Headache 21 30 46 37 Peripheral Neurologic Symptoms/Neuropathy 26 6 21 10 Rash 13 16 30 18 Vomiting 12 14 30 35 Pancreatitis (see below) 1 * <1 * a Percentages based on treated subjects. b Median duration of treatment 48 weeks. * This event was not observed in this study arm. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 27 of 72 Pancreatitis resulting in death was observed in one patient who received VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose. Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 10-12. Table 10: Selected Laboratory Abnormalities from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 VIDEX zidovudine VIDEX zidovudine Parameter n=197 n=212 n=298 n=304 SGOT (AST) (>5 x ULN) 9 4 7 6 SGPT (ALT) (>5 x ULN) 9 6 6 6 Alkaline phosphatase (>5 x ULN) 4 1 1 1 Amylase (≥1.4 x ULN) 17 12 15 5 Uric acid (>12 mg/dL) 3 1 2 1 ULN = upper limit of normal. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 28 of 72 Table 11: Selected Laboratory Abnormalities from Combination Studies (Grades 3-4) Percent of Patientsa AI454-148b START 2b VIDEX + stavudine + nelfinavir zidovudine + lamivudine + nelfinavir VIDEX + stavudine + indinavir zidovudine + lamivudine + indinavir Parameter n=482 n=248 n=102 n=103 Bilirubin (>2.6 x ULN) <1 <1 16 8 SGOT (AST) (>5 x ULN) 3 2 7 7 SGPT (ALT) (>5 x ULN) 3 3 8 5 GGT (>5 x ULN) NC NC 5 2 Lipase (>2 x ULN) 7 2 5 5 Amylase (>2 x ULN) NC NC 8 2 ULN = upper limit of normal. NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Table 12: Selected Laboratory Abnormalities from Combination Studies (All Grades) Percent of Patientsa AI454-148b START 2b Parameter VIDEX + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 VIDEX + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 Bilirubin 7 3 68 55 SGOT (AST) 42 23 53 20 SGPT (ALT) 37 24 50 18 GGT NC NC 28 12 Lipase 17 11 26 19 Amylase NC NC 31 17 NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Observed during Clinical Practice: The following events have been identified during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to VIDEX, or a combination of these factors. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 29 of 72 Body as a Whole – alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders – anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders – anemia, leukopenia, and thrombocytopenia. Liver – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. Metabolic Disorders – diabetes mellitus, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders – Retinal depigmentation and optic neuritis (see WARNINGS). Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with VIDEX. Adverse events and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults. In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND USAGE: Clinical Studies). Retinal changes and optic neuritis have been reported in pediatric patients. OVERDOSAGE There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 30 of 72 hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage VIDEX should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. Adults: The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult patients is dependent on weight as outlined in Table 13. Table 13: Adult Dosing Recommended VIDEX Dose by Patient Weight ≥60 kg <60 kg Preferred dosing 200 mg twice daily 125 mg twice daily Dosing for patients whose management requires once-daily frequency 400 mg once daily 250 mg once daily Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice daily. Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 31 of 72 Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug Interactions). Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should be considered. Concomitant Therapy: Tenofovir disoproxil fumarate. A dose reduction of VIDEX to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended. VIDEX and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). The appropriate dose of VIDEX coadministered with tenofovir in patients with creatinine clearance <60 mL/min has not been established. [See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions; see the complete prescribing information for VIDEX EC (enteric-coated formulation of didanosine) for results of drug interaction studies of tenofovir with reduced doses of the enteric-coated formulation of didanosine.] Renal Impairment: In adult patients with impaired renal function, the dose of VIDEX should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table 14. Table 14: Recommended Dosage of VIDEX in Renal Impairment Recommended VIDEX Dose by Patient Weight Creatinine Clearance (mL/min) ≥60 kg <60 kg ≥60 200 mg twice dailya 125 twice dailya 30-59 200 mg once daily or 100 mg twice daily 150 mg once daily or 75 mg twice daily 10-29 150 mg once daily 100 mg once daily <10 100 mg once daily 75 mg once daily a 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once- This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 32 of 72 Table 14: Recommended Dosage of VIDEX in Renal Impairment daily frequency of administration. Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the clearance of didanosine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered. Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 14. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis. Hepatic Impairment and Toxicity: See WARNINGS. Method of Preparation VIDEX Pediatric Powder for Oral Solution Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a final concentration of 10 mg/mL as follows: 20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle. 10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution with one part of Maximum Strength Mylanta® Liquid for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C). 2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 33 of 72 HOW SUPPLIED VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8-ounce glass bottles containing 2 g or 4 g of VIDEX, respectively. The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any unused portion after 30 days. The NDC numbers for the previously described VIDEX products are: Table 15 NDC NO. Packaging Information Product Strength VIDEX® Pediatric Powder for Oral Solution 0087-6632-41 One bottle per carton 2 g/bottle 0087-6633-41 One bottle per carton 4 g/bottle US Patent Nos.: 4,861,759, 5,254,539, 5,616,566 and 5,880,106. HANDLING AND DISPOSAL Spill, Leak, and Disposal Procedure Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge. Clean surface with soap and water as necessary. Containerize larger spills. There is no single preferred method of disposal of containerized waste. Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Bristol-Myers Squibb Company Princeton, NJ 08543 USA 1196181A3 Revised August 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 34 of 72 Patient Information Rx only VIDEX® (generic name = didanosine also known as ddI) VIDEX® (didanosine) Pediatric Powder for Oral Solution What is VIDEX? VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs to treat children and adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the effects of long-term use of VIDEX. Who should not take VIDEX? Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient, didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 35 of 72 How should I take VIDEX? How should I store it? Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with VIDEX or other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Your pharmacist will prepare the oral solution. Shake the solution well before each use. Store in the refrigerator. Throw away any unused portion after 30 days. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX. Your doctor may also lower your dosage of VIDEX. What should I do if someone takes an overdose of VIDEX? If someone may have taken an overdose of VIDEX, get medical help right away. Contact their doctor or a poison control center. What should I avoid while taking VIDEX? Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX or may increase the possibility or severity of side effects. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Antacids. Since VIDEX is mixed with an antacid, any side effects related to VIDEX’s ingredients may get worse if you also take an antacid. Medicines at the same time you take your VIDEX dose. Some medicines should not be taken at the same time of day that you take VIDEX. Check with your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 36 of 72 Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX. Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX. What are the possible side effects of VIDEX? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX. Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX (including pregnant women). Symptoms that may indicate a liver problem are: • feeling very weak, tired, or uncomfortable, • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX and call your doctor right away. Women, overweight patients, and those who have This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 37 of 72 been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you or a child taking VIDEX has continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful. Ask your child’s doctor how to find out if your child is developing peripheral neuropathy. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for you. If so, you might be started at a lower dose. Special note about other medicines. If you take VIDEX along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children may have similar side effects as adults. Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 38 of 72 breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. Inactive Ingredients: Pediatric Oral Solution: Maximum Strength Mylanta® Liquid. This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Bristol-Myers Squibb Company Princeton, NJ 08543 USA This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. 1196181A3 Revised August 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 39 of 72 Rx only VIDEX® EC (didanosine) VIDEX® EC (didanosine) Delayed-Release Capsules Enteric-Coated Beadlets (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT- EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY, REPRODUCTION, AND FERTILITY). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 40 of 72 DESCRIPTION VIDEX® EC is the brand name for an enteric-coated formulation of didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX EC (didanosine) Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain colloidal silicon dioxide, gelatin, sodium lauryl sulfate, and titanium dioxide. The capsules are imprinted with edible inks. Didanosine is also available in a powder formulation. Please consult the prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for additional information. The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. In VIDEX EC, an enteric coating is used to protect didanosine from degradation by stomach acid. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 41 of 72 MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 42 of 72 Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine. CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 43 of 72 Table 1: Pharmacokinetic Parameters for Didanosine in Adults Parameter Mean ± SD n Oral bioavailabilitya 42 ± 12% 6 Apparent volume of distributionb 1.08 ± 0.22 L/kg 6 CSF-plasma ratiob 21 ± 0.03%c 5 Systemic clearanceb 13.0 ± 1.6 mL/min/kg 6 Renal clearancea 5.5 ± 2.1 mL/min/kg 6 Elimination half-lifea 1.5 ± 0.4 h 6 Urinary recovery of didanosinea 18 ± 8% 6 CSF = cerebrospinal fluid. a following oral administration of a buffered formulation. b following IV administration. c mean ± SE. Comparison of Didanosine Formulations In VIDEX EC, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when the beadlets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid. In healthy volunteers, as well as subjects infected with HIV, the area under the plasma concentration time curve (AUC) is equivalent for didanosine administered as the VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma concentration (CMAX) of didanosine, administered as VIDEX EC, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (TMAX) increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for VIDEX EC. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 44 of 72 Effect of Food on Absorption of Didanosine In the presence of food, the CMAX and AUC for VIDEX EC were reduced by approximately 46% and 19%, respectively, compared to the fasting state. VIDEX EC should be taken on an empty stomach. Special Populations Renal Insufficiency It is recommended that the VIDEX EC (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies using a buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. Table 2: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered Formulation Creatinine Clearance (mL/min) Parameter ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 ND CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 45 of 72 Pediatric Patients The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in pediatric patients. Geriatric Patients Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see PRECAUTIONS: Geriatric Use). Gender The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions (See also PRECAUTIONS: Drug Interactions.) Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions). VIDEX EC Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval (CI) when available, following coadministration of VIDEX EC with a variety of drugs. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 46 of 72 Table 3: Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Valuesa Drug Didanosine Dosage n AUC of Didanosine (90% CI) CMAX of Didanosine (90% CI) tenofovir,b 300 mg once daily with a light mealc 400 mg single dose fasting 2 h before tenofovir 26 ↑ 48% (31, 67%) ↑ 48% (25, 76%) tenofovir,b 300 mg once daily with a light mealc 400 mg single dose with tenofovir and a light meal 25 ↑ 60% (44, 79%) ↑ 64% (41, 89%) tenofovir,b 300 mg once daily with a light mealc 200 mg single dose with tenofovir and a light meal 33 ↑ 16% (6, 27%)d ↓ 12% (−25, 3%)d 250 mg single dose with tenofovir and a light meal 33 ↔ (−13, 5%)e ↓ 20% (−32, −7%)e 325 mg single dose with tenofovir and a light meal 33 ↑ 13% (3, 24%)e ↓ 11% (−24, 4%)e ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min. b tenofovir disoproxil fumarate. c 373 kcalories, 8.2 grams fat. d Compared with VIDEX EC 250 mg administered alone under fasting conditions. e Compared with VIDEX EC 400 mg administered alone under fasting conditions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 47 of 72 Table 4: Results of Drug Interaction Studies with VIDEX EC: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Valuesa Drug Didanosine Dosage n AUC of Coadministered Drug CMAX of Coadministered Drug ciprofloxacin, 750 mg single dose 400 mg single dose 16 ↔ ↔ indinavir, 800 mg single dose 400 mg single dose 23 ↔ ↔ ketoconazole, 200 mg single dose 400 mg single dose 21 ↔ ↔ tenofovir,b 300 mg once daily with a light mealc 400 mg single dose fasting 2 h before tenofovir 25 ↔ ↔ tenofovir,b 300 mg once daily with a light mealc 400 mg single dose with tenofovir and a light meal 25 ↔ ↔ ↔ indicates no change, or mean increase or decrease of <10%. a All studies conducted in healthy volunteers ≥60 kg with creatinine clearance ≥60 mL/min. b tenofovir disoproxil fumarate. c 373 kcalories, 8.2 grams fat. Didanosine Buffered Formulations Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% CI when available, following coadministration of buffered formulations of didanosine with a variety of drugs. Except as noted in table footnotes, the results of these studies may be expected to apply to VIDEX EC. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION (for tenofovir). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 48 of 72 Table 5: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑ 312% ↑ 232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑ 113% ↑ 69% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑ 111% NA methadone, chronic maintenance dose 200 mg single dose 16, 10a ↓ 57% ↓ 66% tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↑ 44% (31, 59%)d ↑ 28% (11, 48%)d No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8e ↓ 16% ↓ 28% indinavir, 800 mg single dose simultaneous 200 mg single dose 16 ↔ ↔ 1 h before didanosine 200 mg single dose 16 ↓ 17% (-27, -7%)d ↓ 13% (-28, 5%)d ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12e ↔ ↓12% loperamide, 4 mg q6h for 1 day 300 mg single dose 12e ↔ ↓23% metoclopramide, 10 mg single dose 300 mg single dose 12e ↔ ↑13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12e ↑14% ↑13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑ 13% (-1, 27%) ↑ 17% (-4, 38%) ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓ 13% (0, 23%) ↓ 16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8e ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8e ↔ ↑ 17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6e ↔ ↔ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 49 of 72 Table 5: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a Parallel-group design; entries are subjects receiving combination and control regimens, respectively. b tenofovir disoproxil fumarate. c patients <60 kg with creatinine clearance ≥60 mL/min. d 90% Cl. e HIV-infected patients. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 50 of 72 Table 6: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days 6a ↔ ↔ delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h 12a 12a ↓ 32%b ↑ 20% ↓ 53%b ↑ 18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12a ↓21% NA nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑12% ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↔ ↑17% sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓ 11% (-17, -4%) ↓ 12% (-28, 8%) tenofovir,c 300 mg once daily 1 h after didanosine 250d or 400 mg once daily for 7 days 14 ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↑ 10% (-9, 34%) ↓ 22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓ 10% (-27, 11%) ↓ 16.5% (-53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b This result is probably related to the buffer and is not expected to occur with VIDEX EC. c tenofovir disoproxil fumarate. d patients <60 kg with creatinine clearance ≥60 mL/min. NA Not available. INDICATIONS AND USAGE VIDEX EC (didanosine) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in adults. (See Clinical Studies.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 51 of 72 Clinical Studies Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV RNA <400 and <50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 7, respectively. Figure 1 Treatment Response Through Week 48, AI454-152 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL and do not meet any criteria for treatment failure (eg, virologic failure or discontinuation for any reason). 0 20 40 60 80 100 0 12 24 36 48 Study Week Percent of Patients ] < 400 c/mL ] < 50 c/mL VIDEX EC+stavudine+nelfinavir, n=258 zidovudine/lamivudine+nelfinavir, n=253 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 52 of 72 Table 7: Outcomes of Randomized Treatment Through Week 48, AI454-152 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX EC + stavudine + zidovudine/lamivudinea + nelfinavir nelfinavir Outcome n=258 n=253 Responderb,c 55% (33%) 56% (33%) Virologic failured 22% (45%) 21% (43%) Death or discontinued due to disease progression 1% (1%) 2% (2%) Discontinued due to adverse event 6% (6%) 7% (7%) Discontinued due to other reasonse 16% (16%) 15% (16%) a Zidovudine/lamivudine combination tablet. b Corresponds to rates at Week 48 in Figure 1. c Subjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated, and other reasons. CONTRAINDICATION VIDEX EC (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any component of the formulation. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT- EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX EC SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 53 of 72 PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX EC IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX EC therapy is recommended. In patients with risk factors for pancreatitis, VIDEX EC should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy, Reproduction, and Fertility). Particular caution should be exercised when administering VIDEX EC to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX EC should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 54 of 72 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients receiving VIDEX EC. (See ADVERSE REACTIONS.) 4. Hepatic Impairment and Toxicity It is unknown if hepatic impairment significantly affects didanosine pharmaco- kinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. The safety and efficacy of VIDEX EC have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. PRECAUTIONS Dosing VIDEX EC should be administered once daily on an empty stomach. Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 55 of 72 patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIDEX EC. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. General Patients with Renal Impairment Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). Hyperuricemia Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (See Patient Information Leaflet) Patients should be informed that a serious toxicity of didanosine, used alone and in combination regimens, is pancreatitis, which may be fatal. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 56 of 72 Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX EC (didanosine). Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX EC may be required if toxicity develops. Patients should be informed that when didanosine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when didanosine is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX EC toxicities. VIDEX EC is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX EC. Patients should be advised that VIDEX EC therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX EC are unknown at this time. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3-6). The clinical recommendations based on the results of these studies are listed in Table 8. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 57 of 72 Table 8: Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX EC Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. tenofovir disoproxil fumarate ↑ didanosine concentration A dose reduction of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily taken together with tenofovir and a light meal (≤400 kcalories and ≤20% fat) or in the fasted state is recommended. Patients should be monitored for didanosine-associated toxicities and clinical response (see below). ↑ indicates increase. ↓ indicates decrease. Coadministration of VIDEX EC with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Predicted drug interactions with VIDEX EC are listed in Table 9. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 58 of 72 Table 9: Predicted Drug Interactions with VIDEX EC Drug or Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Ribavirin ↑ risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Coadministration is not recommended (see below). ↑ indicates increase. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Nucleoside/nucleotide analogues Tenofovir disoproxil fumarate. Exposure to didanosine is increased when coadministered with tenofovir (see Tables 3, 5, and 8). Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir with VIDEX EC should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. VIDEX EC should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS). Administration of reduced doses of VIDEX EC with tenofovir and a light meal resulted in didanosine exposures (AUC) similar to the recommended doses of VIDEX EC given alone in the fasted state (see Table 3). Therefore, when administered with tenofovir, a dose reduction of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily is recommended, and both drugs may be taken together with a light meal (≤400 kcalories, ≤20% fat) or in the fasted state (see DOSAGE AND ADMINISTRATION). Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 59 of 72 Ribavirin. Exposure to the active metabolite of didanosine (dideoxyadenosine 5'- triphosphate) is increased when didanosine is coadministered with ribavirin (see Table 9). Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine and ribavirin is not recommended. Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 60 of 72 reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast- feed if they are receiving VIDEX EC (didanosine). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 61 of 72 Pediatric Use The safety and efficacy of VIDEX EC in pediatric patients have not been established. Please consult the complete prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for dosage and administration of didanosine to pediatric patients. Geriatric Use In an Expanded Access Program using a buffered formulation of didanosine for the treatment of advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see WARNINGS). Clinical studies of didanosine, including those for VIDEX EC, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). ADVERSE REACTIONS A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with VIDEX EC in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy (see WARNINGS and PRECAUTIONS). Selected clinical adverse events that occurred in a study of VIDEX EC in combination with other antiretroviral agents are provided in Table 10. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 62 of 72 Table 10: Selected Clinical Adverse Events, Study AI454-152a Percent of Patientsb VIDEX EC + stavudine + nelfinavir zidovudine/ lamivudinec + nelfinavir Adverse Events n=258 n=253 Diarrhea 57 58 Peripheral Neurologic Symptoms/Neuropathy 25 11 Nausea 24 36 Headache 22 17 Rash 14 12 Vomiting 14 19 Pancreatitis (see below) <1 * a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group. b Percentages based on treated patients. c Zidovudine/lamivudine combination tablet. * This event was not observed in this study arm. In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. Selected laboratory abnormalities that occurred in a study of VIDEX EC in combination with other antiretroviral agents are shown in Table 11. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 63 of 72 Table 11: Selected Laboratory Abnormalities, Study AI454-152a Percent of Patientsb VIDEX EC + stavudine + nelfinavir n=258 zidovudine/lamivudinec + nelfinavir n=253 Parameter Grades 3-4d All Grades Grades 3-4d All Grades SGOT (AST) 5 46 5 19 SGPT (ALT) 6 44 5 22 Lipase 5 23 2 13 Bilirubin <1 9 <1 3 a Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group. b Percentages based on treated patients. c Zidovudine/lamivudine combination tablet. d >5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN = upper limit of normal). Observed During Clinical Practice The following events have been identified during postapproval use of didanosine buffered formulations. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors. Body as a Whole – abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders – anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders – anemia, leukopenia, and thrombocytopenia. Liver – symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 64 of 72 Metabolic Disorders – diabetes mellitus, elevated serum alkaline phosphatase level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders – myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders – Retinal depigmentation and optic neuritis (see WARNINGS). OVERDOSAGE There is no known antidote for didanosine overdosage. In phase 1 studies, in which buffered formulations of didanosine were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage Adults VIDEX EC (didanosine) should be administered on an empty stomach. VIDEX EC Delayed-Release Capsules should be swallowed intact. The recommended daily dose is dependent on body weight and is administered as one capsule given on a once-daily schedule as outlined in Table 12. Table 12: Dosing of VIDEX EC Delayed-Release Capsules Patient Weight Dosage ≥60 kg 400 mg once daily <60 kg 250 mg once daily This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 65 of 72 Pediatric Patients VIDEX EC has not been studied in pediatric patients. Please consult the complete prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for dosage and administration of didanosine to pediatric patients. Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX EC use should be discontinued in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug Interactions). Based on data with buffered didanosine formulations, patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX EC after resolution of the symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after resumption of VIDEX EC, permanent discontinuation of VIDEX EC should be considered. Concomitant Therapy Tenofovir disoproxil fumarate. A dose reduction of VIDEX EC to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily taken together with tenofovir and a light meal (≤400 kcalories, ≤20% fat) or in the fasted state is recommended. The appropriate dose of VIDEX EC coadministered with tenofovir in patients with creatinine clearance <60 mL/min has not been established. (See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions.) Renal Impairment Dosing recommendations for VIDEX EC and VIDEX Pediatric Powder for Oral Solution are different for patients with renal impairment. Please consult the complete prescribing information on administration of VIDEX (didanosine) Pediatric Powder for Oral Solution to patients with renal impairment. In adult patients with impaired renal function, the dose of VIDEX EC should be adjusted to compensate for the slower rate of elimination. The recommended doses and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 66 of 72 dosing intervals of VIDEX EC in adult patients with renal insufficiency are presented in Table 13. Table 13: Recommended Dosage of VIDEX EC in Renal Impairment by Body Weighta Dosage Creatinine Clearance (mL/min) ≥60 kg <60 kg ≥60 400 once daily 250 once daily 30-59 200 once daily 125 once daily 10-29 125 once daily 125 once daily <10 125 once daily b a Based on studies using a buffered formulation of didanosine. b Not suitable for use in patients <60 kg with CLcr <10 mL/min. An alternate formulation of didanosine should be used. Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to administer a supplemental dose of didanosine following hemodialysis. Hepatic Impairment and Toxicity: See WARNINGS. HOW SUPPLIED VIDEX® EC (didanosine) Delayed-Release Capsules are white, opaque capsules that are packaged in bottles with child-resistant closures as described in Table 14. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 67 of 72 Table 14: VIDEX EC Delayed-Release Capsules 125 mg capsule imprinted with BMS 125 mg 6671 in Tan NDC No. 0087-6671-17 30 capsules/bottle 200 mg capsule imprinted with BMS 200 mg 6672 in Green NDC No. 0087-6672-17 30 capsules/bottle 250 mg capsule imprinted with BMS 250 mg 6673 in Blue NDC No. 0087-6673-17 30 capsules/bottle 400 mg capsule imprinted with BMS 400 mg 6674 in Red NDC No. 0087-6674-17 30 capsules/bottle The capsules should be stored in tightly closed containers at 25° C (77° F). Excursions between 15° and 30° C (59° and 86° F) are permitted [see USP Controlled Room Temperature]. HANDLING AND DISPOSAL Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. US Patent Nos: 4,861,759, 5,254,539, 5,616,566, and 5,880,106 (didanosine). Patent also Pending (didanosine capsules). Bristol-Myers Squibb Company Princeton, NJ 08543 USA 1196180A3 Revised August 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 68 of 72 PATIENT INFORMATION Rx only VIDEX® EC (generic name = didanosine also known as ddI) VIDEX® EC (didanosine) Delayed-Release Capsules Enteric-Coated Beadlets What is VIDEX EC? VIDEX EC (pronounced VY dex ee see) is a prescription medicine used in combination with other drugs to treat adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX EC belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX EC helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX EC will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX EC, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX EC does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the antiviral response of long-term use of VIDEX EC. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 69 of 72 In VIDEX EC, an enteric coating is used to protect the medicine while it is in your stomach since stomach acids can break it down. The enteric coating dissolves when the medicine reaches your small intestine. Who should not take VIDEX EC? Do not take VIDEX EC if you are allergic to any of its ingredients, including its active ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. Because it has only been studied in adults, VIDEX EC is not recommended for children. How should I take VIDEX EC? How should I store it? VIDEX EC should only be taken once daily. Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with VIDEX EC or other medicines. Take VIDEX EC on an empty stomach. Do not take VIDEX EC with food. Swallow the capsule whole; do not open it. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Store capsules in a tightly closed container at room temperature away from heat and out of the reach of children and pets. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX EC. Your doctor may also lower your dosage of VIDEX EC. What should I do if someone takes an overdose of VIDEX EC? If someone may have taken an overdose of VIDEX EC, get medical help right away. Contact their doctor or a poison control center. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 70 of 72 What should I avoid while taking VIDEX EC? Alcohol. Do not drink alcohol while taking VIDEX EC since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX EC or may increase the possibility or severity of side effects. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Pregnancy. It is not known if VIDEX EC can harm a human fetus. Also, pregnant women have experienced serious side effects when taking didanosine (the active ingredient in VIDEX EC) in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX EC should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX EC. Nursing. Studies have shown didanosine (the active ingredient in VIDEX EC) is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX EC. What are the possible side effects of VIDEX EC? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you develop stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX EC therapy, let your doctor know if you have ever had pancreatitis. This condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX EC. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 71 of 72 Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX EC (including pregnant women). Symptoms that may indicate a liver problem are: • feeling very weak, tired, or uncomfortable, • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX EC and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX EC. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX EC may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you have continuing numbness, tingling, or pain in the feet or hands. Before starting VIDEX EC therapy, let your doctor know if you have ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking VIDEX EC. After stopping VIDEX EC, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX EC is right for you. If so, you might be started at a lower dose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 20-154/S-050 NDA 20-155/S-039 NDA 20-156/S-040 NDA 21-183/S-016 Page 72 of 72 Special note about other medicines. If you take VIDEX EC along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX EC in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. Other side effects: The most common side effects in adults taking VIDEX EC in combination with other HIV drugs included diarrhea, nausea, headache, vomiting, and rash. Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. Inactive Ingredients: Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, talc, colloidal silicon dioxide, gelatin, sodium lauryl sulfate, and titanium dioxide. This medicine was prescribed for your particular condition. Do not use VIDEX EC for another condition or give it to others. Keep VIDEX EC and all medicines out of the reach of children. Throw away VIDEX EC when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX EC. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about VIDEX EC, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Bristol-Myers Squibb Company Princeton, NJ 08543 USA This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. 1196180A3 Revised August 2006 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:53.686294	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020154s50,20155s39,20156s40,21183s16lbl.pdf', 'application_number': 20154, 'submission_type': 'SUPPL ', 'submission_number': 50}
12,270	Page 4 of 39 Rx only VIDEX (didanosine) VIDEX (didanosine) Chewable/Dispersible Buffered Tablets VIDEX (didanosine) Buffered Powder for Oral Solution VIDEX (didanosine) Pediatric Powder for Oral Solution (Patient Information Leaflet Included) WARNING FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (SEE WARNINGS). LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING DIDANOSINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANOSINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK. (SEE WARNINGS AND PRECAUTIONS: PREGNANCY.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 5 of 39 DESCRIPTION VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate. VIDEX Buffered Powder for Oral Solution is supplied for oral administration in single- dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively. Didanosine is also available as an enteric-coated formulation (VIDEX® EC Delayed- Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine). The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is: Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 6 of 39 MICROBIOLOGY Mechanism of Action Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation. In Vitro HIV Susceptibility The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine- treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 7 of 39 Cross-resistance HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established. CLINICAL PHARMACOLOGY Animal Toxicology Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of VIDEX (didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of VIDEX and other nucleoside analogues. Pharmacokinetics The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 8 of 39 Table 1: Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients Pediatric Patientsb Parameter Adult Patientsa n 8 months to 19 years n 2 weeks to 4 months n Oral bioavailability (%) 42 ± 12 6 25 ± 20 46 ND Apparent volume of distributionc (L/m2) 43.70 ± 8.90 6 28 ± 15 49 ND CSF-plasma ratiod 21 ± 0.03%e 5 46% (range 12-85%) 7 ND Systemic clearancec (mL/min/m2) 526 ± 64.7 6 516 ± 184 49 ND Renal clearancef (mL/min/m2) 223 ± 85.0 6 240 ± 90 15 ND Apparent oral clearanceg (mL/min/m2) 1252 ± 154 6 2064 ± 736 48 1353 ± 759 41 Elimination half-lifef (h) 1.5 ± 0.4 6 0.8 ± 0.3 60 1.2 ± 0.3 21 Urinary recovery of didanosinef (%) 18 ± 8 6 18 ± 10 15 ND CSF = cerebrospinal fluid, ND = not determined. a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m2. b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m2 and half-life was 2.0 ± 0.7 h. c Following IV administration. d Following IV administration in adults and IV or oral administration in pediatric patients. e Mean ± SE. f Following oral administration. g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral bioavailability estimate. Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (CMAX) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 9 of 39 Special Populations Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies in adults indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. Table 2: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose Creatinine Clearance (mL/min) Parameter ≥ 90 (n=12) 60-90 (n=6) 30-59 (n=6) 10-29 (n=3) Dialysis Patients (n=11) CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 NDa CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174 CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10 T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2 a ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children above 8 months old. For information on controlled clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies and PRECAUTIONS: Pediatric Use. Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age. Gender: The effects of gender on didanosine pharmacokinetics have not been studied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 10 of 39 Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95% confidence interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic interactions were observed. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 11 of 39 Table 3: Results of Drug Interaction Studies: Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) allopurinol renally impaired, 300 mg/day 200 mg single dose 2 ↑312% ↑232% healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑113% ↑69% ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8a ↓16% ↓28% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12 ↑111% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↔ ↓17% (-27, - 7%)b ↔ ↓13% (-28, 5%)b ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↔ ↓12% methadone, chronic maintenance dose 200 mg single dose 16,10c ↓57% ↓66% tenofovir,d,e 300 mg once daily 1 h after didanosine 250f or 400 mg once daily for 7 days 14 ↑44% (31, 59%)b ↑28% (11, 48%)b No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Didanosine (95% CI) CMAX of Didanosine (95% CI) loperamide, 4 mg q6h for 1 day 300 mg single dose 12a ↔ ↓23% metoclopramide, 10 mg single dose 300 mg single dose 12a ↔ ↑13% ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↑14% ↑13% rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑13% (-1, 27%) ↑17% (-4, 38%) ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓13% (0, 23%) ↓16% (5, 26%) stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10 ↔ ↔ sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↔ ↑17% (-23, 77%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↔ ↔ ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b 90% CI. c Parallel-group design; entries are subjects receiving combination and control regimens, respectively. d tenofovir disoproxil fumarate. e In a drug interaction study with the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir, the AUC and CMAX of didanosine each increased 48% when VIDEX EC was administered in the fasting state 2 hours before tenofovir with a light meal. The AUC and CMAX of didanosine increased 60% and 64%, respectively, when VIDEX EC was administered together with tenofovir and a light meal. f patients less than 60 kg. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 12 of 39 Table 4: Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions) Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) ciprofloxacin 750 mg q12h for 3 days, 2 h before didanosine 750 mg single dose 200 mg q12h for 3 days buffered placebo tablet 8a 12 ↓26% ↓98% ↓16% ↓93% delavirdine, 400 mg single dose simultaneous 1 h before didanosine 125 or 200 mg q12h 125 or 200 mg q12h 12a 12a ↓32% ↑20% ↓53% ↑18% ganciclovir, 1000 mg q8h, 2 h after didanosine 200 mg q12h 12a ↓21% NA indinavir, 800 mg single dose simultaneous 1 h before didanosine 200 mg single dose 200 mg single dose 16 16 ↓84% ↓11% ↓82% ↓4% ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12a ↓14% ↓20% nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑12% ↔ No Clinically Significant Interaction Observed Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) CMAX of Coadministered Drug (95% CI) dapsone, 100 mg single dose 200 mg q12h for 14 days 6a ↔ ↔ ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓16% ↔ ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↔ ↔ stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↔ ↑17% sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓11% (-17, -4%) ↓12% (-28, 8%) tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↔ ↔ trimethoprim, 200 mg single dose 200 mg single dose 8a ↑10% (-9, 34%) ↓22% (-59, 49%) zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓10% (-27, 11%) ↓16.5% (-53, 47%) ↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. a HIV-infected patients. b tenofovir disoproxil fumarate. c patients less than 60 kg. NA Not available. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 13 of 39 INDICATIONS AND USAGE VIDEX in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection (see Clinical Studies). Clinical Studies Combination Therapy START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and increases in CD4 cell counts through 48 weeks. Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks are shown in Figure 1 and Table 5. Figure 1: Treatment Response Through Week 48, AI454-148 Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original study medication (except stavudine-zidovudine switches), and have not experienced an AIDS-defining event. 0 20 40 60 80 100 0 8 16 24 32 40 48 Study Week Percent of patients ] < 400 c/mL ] < 50 c/mL VIDEX+stavudine+nelfinavir (n=503) zidovudine+lamivudine+nelfinavir (n=253) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 14 of 39 Table 5: Outcomes of Randomized Treatment through Week 48, AI454-148 Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL) VIDEX/stavudine/nelfinavir lamivudine/zidovudine/nelfinavir Week 48 Status n=503 n=253 Responder a 50* (34) 59 (47) Virologic failureb 36 (57) 32 (48) Death or disease progression <1 (<1) 1 (<1) Discontinued due to adverse events 4 (2) 2 (<1) Discontinued due to other reasonsc 6 (3) 4 (2) Never initiated treatment 4 (4) 2 (2) p <0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test. a Patients achieved virologic response [two consecutive viral loads <400 (<50) copies/mL] and maintained it to Week 48. b Includes viral rebound and failing to achieve confirmed <400 (<50) copies/mL by Week 48. c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy. Monotherapy The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were similar between the treatment groups. Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death compared with those treated with zidovudine alone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 15 of 39 Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including VIDEX, was time limited. CONTRAINDICATION VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulations. WARNINGS 1. Pancreatitis FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS. When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. In pediatric phase 1 studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX use should be suspended in pediatric This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 16 of 39 patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis. 2. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy). Particular caution should be exercised when administering VIDEX to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 3. Retinal Changes and Optic Neuritis Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.) PRECAUTIONS Frequency of Dosing The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see INDICATIONS AND USAGE: Clinical Studies). VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 17 of 39 Peripheral Neuropathy Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine (see ADVERSE REACTIONS). Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. General Patients with Phenylketonuria: VIDEX Chewable/Dispersible Buffered Tablets contain the following quantities of phenylalanine: Table 6 All Strengths Phenylalanine per 2-tablet dose 73 mg Phenylalanine per tablet 36.5 mg Patients on Sodium-Restricted Diets: VIDEX Buffered Powder for Oral Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains 1380 mg sodium. Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to patients with significant renal impairment, particularly after prolonged dosing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 18 of 39 Patients with Hepatic Impairment: It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. Hyperuricemia: VIDEX has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail. Information for Patients (See Patient Information Leaflet.) Patients should be informed that a serious toxicity of VIDEX used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX may be required if toxicity develops. Patients should be informed that when VIDEX is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when VIDEX is used alone. These patients should be followed closely. Patients should be cautioned about the use of medications or other substances, including alcohol, that may exacerbate VIDEX toxicities. Patients should be advised that to ensure proper acid neutralization in the stomach they must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the risk of gastrointestinal side effects from excess antacid, patients should take no more than four VIDEX tablets at each dose. VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX. Patients should be advised that This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 19 of 39 VIDEX therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of VIDEX are unknown at this time. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions) Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY: Drug Interactions (Tables 3 and 4). The clinical recommendations based on the results of these studies are listed in Table 7. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 20 of 39 Table 7: Established Drug Interactions with VIDEX Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment allopurinol ↑ didanosine concentration Coadministration not recommended. Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction) Drug Effect Clinical Comment ciprofloxacin ↓ ciprofloxacin concentration Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin. delavirdine ↓ delavirdine concentration Administer VIDEX 1 hour after delavirdine. ganciclovir ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. indinavir ↓ indinavir concentration Administer VIDEX 1 hour after indinavir. methadone ↓ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX. tenofovir disoproxil fumarate ↑ didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Use with caution and monitor closely for didanosine-associated toxicities (see below). ↑ indicates increase. ↓ indicates decrease. Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX formulations either contain buffers or are mixed with antacids before administration, interactions may be anticipated with drugs whose absorption can be affected by the level of acidity in the stomach and with drugs that have been demonstrated to interact with antacids containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in Table 8. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 21 of 39 Table 8: Predicted Drug Interactions with VIDEX Use with Caution, Risk of Adverse Reactions May Be Increased Drug or Drug Class Effect Clinical Comment Drugs that may cause pancreatic toxicity ↑ risk of pancreatitis Use only with extreme caution.a Neurotoxic drugs ↑ risk of neuropathy Use with caution.b Antacids containing magnesium or aluminum ↑ side effects associated with antacid components Use caution with VIDEX Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution. Ribavirin ↑ risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Use with caution and monitor closely for didanosine-associated toxicities (see below). Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX Drug Class Effect Clinical Comment Azole antifungals ↓ ketoconazole or itraconazole concentration Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX. Quinolone antibiotics (see also ciprofloxacin in Table 7) ↓ quinolone concentration Consult package insert of the quinolone. Tetracycline antibiotics ↓ antibiotic concentration Consult package insert of the tetracycline. ↑ indicates increase. ↓ indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended (see WARNINGS: Pancreatitis). b See PRECAUTIONS: Peripheral Neuropathy. Tenofovir disoproxil fumarate or ribavirin. Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with either tenofovir (see Tables 3 and 7) or ribavirin (see Table 8). Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir or ribavirin with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS). Carcinogenesis and Mutagenesis Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 22 of 39 were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure. Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses. Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays. Pregnancy, Reproduction, and Fertility Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 23 of 39 pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV- infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIDEX. Pediatric Use Use of VIDEX in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of VIDEX in adults and pediatric patients (see INDICATIONS AND USAGE: Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. Geriatric Use In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) (see This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 24 of 39 WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment). ADVERSE REACTIONS A SERIOUS TOXICITY OF VIDEX (didanosine) IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS; RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS). When VIDEX is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when VIDEX is used alone. Thus, patients treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and hepatotoxicity (see WARNINGS). Patients treated with VIDEX in combination with stavudine may also be at increased risk for peripheral neuropathy (see PRECAUTIONS). Adults: Selected clinical adverse events that occurred in adult patients in clinical studies with VIDEX are provided in Tables 9 and 10. Table 9: Selected Clinical Adverse Events from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 Adverse Events VIDEX n=197 zidovudine n=212 VIDEX n=298 zidovudine n=304 Diarrhea 19 15 28 21 Peripheral Neurologic Symptoms/Neuropathy 17 14 20 12 Rash/Pruritus 7 8 9 5 Abdominal Pain 13 8 7 8 Pancreatitis 7 3 6 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 25 of 39 Table 10: Selected Clinical Adverse Events from Combination Studies Percent of Patientsa AI454-148b START 2b Adverse Events VIDEX + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 VIDEX + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 Diarrhea 70 60 45 39 Nausea 28 40 53 67 Headache 21 30 46 37 Peripheral Neurologic Symptoms/Neuropathy 26 6 21 10 Rash 13 16 30 18 Vomiting 12 14 30 35 Pancreatitis (see below) 1 * <1 * a Percentages based on treated subjects. b Median duration of treatment 48 weeks. * This event was not observed in this study arm. Pancreatitis resulting in death was observed in one patient who received VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose. Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 11-13. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 26 of 39 Table 11: Selected Laboratory Abnormalities from Monotherapy Studies Percent of Patients ACTG 116A ACTG 116B/117 VIDEX zidovudine VIDEX zidovudine Parameter n=197 n=212 n=298 n=304 SGOT (AST) (>5 x ULN) 9 4 7 6 SGPT (ALT) (>5 x ULN) 9 6 6 6 Alkaline phosphatase (>5 x ULN) 4 1 1 1 Amylase (≥1.4 x ULN) 17 12 15 5 Uric acid (>12 mg/dL) 3 1 2 1 ULN = upper limit of normal. Table 12: Selected Laboratory Abnormalities from Combination Studies (Grades 3-4) Percent of Patientsa AI454-148b START 2b VIDEX + stavudine + nelfinavir zidovudine + lamivudine + nelfinavir VIDEX + stavudine + indinavir zidovudine + lamivudine + indinavir Parameter n=482 n=248 n=102 n=103 Bilirubin (>2.6 x ULN) <1 <1 16 8 SGOT (AST) (>5 x ULN) 3 2 7 7 SGPT (ALT) (>5 x ULN) 3 3 8 5 GGT (>5 x ULN) NC NC 5 2 Lipase (>2 x ULN) 7 2 5 5 Amylase (>2 x ULN) NC NC 8 2 ULN = upper limit of normal. NC=Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 27 of 39 Table 13: Selected Laboratory Abnormalities from Combination Studies (All Grades) Percent of Patientsa I454-148b START 2b Parameter VIDEX + stavudine + nelfinavir n=482 zidovudine + lamivudine + nelfinavir n=248 VIDEX + stavudine + indinavir n=102 zidovudine + lamivudine + indinavir n=103 Bilirubin 7 3 68 55 SGOT (AST) 42 23 53 20 SGPT (ALT) 37 24 50 18 GGT NC NC 28 12 Lipase 17 11 26 19 Amylase NC NC 31 17 NC = Not Collected. a Percentages based on treated subjects. b Median duration of treatment 48 weeks. Observed during Clinical Practice: The following events have been identified during postapproval use of VIDEX (didanosine). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to VIDEX, or a combination of these factors. Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution). Digestive Disorders- anorexia, dyspepsia, and flatulence. Exocrine Gland Disorders – pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes. Hematologic Disorders - anemia, leukopenia, and thrombocytopenia. Liver - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure. Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia. Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy. Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 28 of 39 Pediatric Patients: In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with VIDEX. Adverse events and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults. In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine (see INDICATIONS AND USAGE: Clinical Studies). Retinal changes and optic neuritis have been reported in pediatric patients. OVERDOSAGE There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis (see CLINICAL PHARMACOLOGY: Pharmacokinetics). DOSAGE AND ADMINISTRATION Dosage All VIDEX formulations should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen, patients must take at least two of the appropriate strength tablets at each dose to provide adequate buffering and prevent gastric acid degradation of didanosine. Because of the need for adequate buffering, the 200-mg strength tablet should only be used as a component of a once-daily regimen. To reduce the risk of gastrointestinal side effects, patients should take no more than four tablets at each dose. Adults: The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 29 of 39 (see INDICATIONS AND USAGE: Clinical Studies). The daily dose in adult patients is dependent on weight as outlined in Table 14. Table 14: Adult Dosing Patient Weight VIDEX Tabletsa VIDEX Buffered Powderb Preferred dosing ≥60 kg 200 mg twice daily 250 mg twice daily < 60 kg 125 mg twice daily 167 mg twice daily Dosing for patients whose management requires once-daily frequency ≥ 60 kg 400 mg once daily b < 60 kg 250 mg once daily b a The 200-mg strength tablet should only be used as a component of a once-daily regimen. b Not suitable for once-daily dosing except for patients with renal impairment. See Table 15. Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients between 2 weeks and 8 months of age is 100 mg/m2 twice daily, and the recommended VIDEX dose for pediatric patients older than 8 months is 120 mg/m2 twice daily. Dosing recommendations for VIDEX in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients. Dose Adjustment Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in patients with confirmed pancreatitis (see WARNINGS and PRECAUTIONS: Drug Interactions). Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should be considered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 30 of 39 Renal Impairment: In adult patients with impaired renal function, the dose of VIDEX should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table 15. Table 15: Recommended Dosage of VIDEX in Renal Impairment ≥ 60 kg < 60 kg Creatinine Clearance (mL/min) Tableta (mg) Buffered Powderb (mg) Tableta (mg) Buffered Powderb (mg) ≥60 200 twice dailyc 250 twice daily 125 twice dailyc 167 twice daily 30-59 200 once daily or 100 twice daily 100 twice daily 150 once daily or 75 twice daily 100 twice daily 10-29 150 once daily 167 once daily 100 once daily 100 once daily <10 100 once daily 100 once daily 75 once daily 100 once daily a VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose; different strengths of tablets may be combined to yield the recommended dose. b VIDEX Buffered Powder for Oral Solution. c 400 mg once daily (≥60 kg) or 250 mg once daily (<60 kg) for patients whose management requires once- daily frequency of administration. Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the clearance of didanosine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered. Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis: For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis. Hepatic Impairment: See WARNINGS and PRECAUTIONS. Method of Preparation VIDEX Chewable/Dispersible Buffered Tablets Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 31 of 39 water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable at room temperature, 62° to 73°F (17° to 23°C), for up to one hour. VIDEX Buffered Powder for Oral Solution 1. Open packet carefully and pour contents into a container with approximately 4 ounces of drinking water. Do not mix with fruit juice or other acid-containing liquid. 2. Stir until the powder completely dissolves (approximately 2 to 3 minutes). 3. Drink the entire solution immediately. VIDEX Pediatric Powder for Oral Solution Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a final concentration of 10 mg/mL as follows: 20 mg/mL Initial Solution: Constitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle. 10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution with one part of either Mylanta® Double Strength Liquid, Extra Strength Maalox® Plus Suspension, or Maalox ® TC Suspension for a final dispensing concentration of 10 mg VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This admixture is stable for 30 days under refrigeration, 36° to 46° F (2° to 8° C). 2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed container in the refrigerator, 36° to 46° F (2° to 8° C), up to 30 days. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 32 of 39 HOW SUPPLIED VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets are round, off white to light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on one side and the product strength on the other. The tablets are available in the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with child-resistant closures. The tablets should be stored in tightly closed bottles at 59° to 86° F (15° to 30 °C). If dispersed in water, the dose may be held for up to 1 hour at ambient temperature. VIDEX (didanosine) Buffered Powder for Oral Solution is supplied in single-dose, child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each product strength provides a sweetened, buffered solution of VIDEX. The packets should be stored at 59° to 86° F (15° to 30° C). After dissolving in water, the solution may be stored at ambient room temperature for up to 4 hours. VIDEX (didanosine) Pediatric Powder for Oral Solution is supplied in 4- and 8- ounce glass bottles containing 2 g or 4 g of VIDEX, respectively. The bottles of powder should be stored at 59° to 86° F (15° to 30° C). The VIDEX admixture may be stored up to 30 days in a refrigerator, 36° to 46° F (2° to 8° C). Discard any unused portion after 30 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 33 of 39 The NDC numbers for the previously described VIDEX products are: Table 16 NDC NO. Packaging Information Product Strength VIDEX Chewable/Dispersible Buffered Tablets 0087-6650-01 60 tablets/bottle 25 mg/tablet 0087-6651-01 60 tablets/bottle 50 mg/tablet 0087-6652-01 60 tablets/bottle 100 mg/tablet 0087-6653-01 60 tablets/bottle 150 mg/tablet 0087-6665-15 60 tablets/bottle 200 mg/tablet VIDEX Buffered Powder for Oral Solution 0087-6614-43 One single-dose foil packet* 100 mg/packet 0087-6615-43 One single-dose foil packet* 167 mg/packet 0087-6616-43 One single-dose foil packet* 250 mg/packet VIDEX Pediatric Powder for Oral Solution 0087-6632-41 One bottle per carton 2 g/bottle 0087-6633-41 One bottle per carton 4 g/bottle * Packaged as 30 packets per carton. US Patent Nos.: 4,861,759 and 5,616,566. HANDLING AND DISPOSAL Spill, Leak, and Disposal Procedure Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge. Clean surface with soap and water as necessary. Containerize larger spills. There is no single preferred method of disposal of containerized waste. Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA XXXXXX Revised _____________________ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 34 of 39 PATIENT INFORMATION Rx only VIDEX® (generic name = didanosine also known as ddI) VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets VIDEX® (didanosine) Buffered Powder for Oral Solution VIDEX® (didanosine) Pediatric Powder for Oral Solution What is VIDEX? VIDEX (pronounced VY dex) is a prescription medicine used in combination with other drugs to treat children and adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). VIDEX belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, VIDEX helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections. VIDEX will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking VIDEX, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur. VIDEX does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids. There is limited information on the effects of long-term use of VIDEX. Who should not take VIDEX? Do not take VIDEX if you are allergic to any of its ingredients, including its active ingredient, didanosine and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 35 of 39 How should I take VIDEX? How should I store it? Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with VIDEX or other medicines. Take VIDEX on an empty stomach - that means at least 30 minutes before or 2 hours after eating. Do not take VIDEX with food. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Chewable/Dispersible Tablets: Each VIDEX tablet contains antacid. Each time you take VIDEX, you must take at least two, but not more than four, tablets. This is because VIDEX tablets contain an antacid to reduce the amount of acid in your stomach. If you have too much acid, the medicine will break down. However, too much antacid may cause stomach problems. —DO NOT swallow VIDEX tablets whole. Chew the tablets well or mix them in water. Many patients drop the tablets in at least one ounce of water and stir well before swallowing. If you choose to mix the tablets in water, you may add one ounce (2 tablespoons) of clear apple juice to the mixture for flavor (do not use any other kind of juice). —Store tablets in a tightly closed container at room temperature away from heat and out of the reach of children and pets. Do NOT store the tablets in a damp place such as a bathroom medicine cabinet or near the kitchen sink. Buffered Powder for Oral Solution: Pour the contents of a packet into a glass with 4 ounces (1/2 measuring cup) of water. Stir until completely dissolved. Drink the entire solution right away. Do not mix with fruit juice. Store packets at room temperature before use. Pediatric Oral Solution: Your pharmacist will prepare the oral solution. Shake the solution well before each use. Store in the refrigerator. Throw away any unused portion after 30 days. If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take VIDEX. Your doctor may also lower your dosage of VIDEX. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 36 of 39 What should I do if someone takes an overdose of VIDEX? If someone may have taken an overdose of VIDEX, get medical help right away. Contact their doctor or a poison control center. What should I avoid while taking VIDEX? Alcohol. Do not drink alcohol while taking VIDEX since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage. Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of VIDEX. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor. Antacids. Since VIDEX contains some of the same ingredients found in antacids, any side effects related to VIDEX’s ingredients may get worse if you also take an antacid. Medicines at the same time you take your VIDEX dose. Some medicines should not be taken at the same time of day that you take VIDEX. Check with your doctor. Pregnancy. It is not known if VIDEX can harm a human fetus. Also, pregnant women have experienced serious side effects when taking VIDEX in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. VIDEX should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking VIDEX. Nursing. Studies have shown VIDEX is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking VIDEX. What are the possible side effects of VIDEX? Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you or a child taking VIDEX develops stomach pain, nausea, or vomiting. These can be signs of pancreatitis. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had pancreatitis. This This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 37 of 39 condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine or hydroxyurea. If you get pancreatitis, your doctor will tell you to stop taking VIDEX. Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking VIDEX (including pregnant women). Symptoms that may indicate a liver problem are: • feeling very weak, tired, or uncomfortable, • unusual or unexpected stomach discomfort, • feeling cold, • feeling dizzy or lightheaded, • suddenly developing a slow or irregular heartbeat. Lactic acidosis is a medical emergency that must be treated in a hospital. If you notice any of these symptoms or if your medical condition changes, stop taking VIDEX and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking VIDEX. You should be especially careful if you have a history of heavy alcohol use or a liver problem. Vision changes. VIDEX may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision. Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you or a child taking VIDEX has continuing numbness, tingling, or pain in the feet or hands. A child may not recognize these symptoms or know to tell you that his or her feet or hands are numb, burning, tingling, or painful. Ask your child’s doctor how to find out if your child is developing peripheral neuropathy. Before starting VIDEX therapy, let your doctor know if you or a child for whom it has been prescribed has ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 38 of 39 get peripheral neuropathy, your doctor will tell you to stop taking VIDEX. After stopping VIDEX, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting VIDEX is right for you. If so, you might be started at a lower dose. Special note about other medicines. If you take VIDEX along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using VIDEX in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine and hydroxyurea) may increase your chance of having these side effects. Other side effects: The most common side effects in adults taking VIDEX are diarrhea, neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children may have similar side effects as adults. Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time. What else should I know about VIDEX? If you should limit sodium (salt) intake: Each single-dose packet of Buffered Powder for Oral Solution contains 1380 mg of sodium. Each Chewable/Dispersible Tablet contains 264.5 mg of sodium. If you have phenylketonuria: Each Chewable/Dispersible Tablet contains 36.5 mg of phenylalanine. Inactive Ingredients: Chewable/Dispersible Tablets: calcium carbonate, magnesium hydroxide, aspartame, sorbitol, mandarin orange flavor, polyplasdone, microcrystalline cellulose, and magnesium stearate. Buffered Powder for Oral Solution: citrate-phosphate buffer (dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Page 39 of 39 Pediatric Oral Solution: Mylanta Double Strength Liquid, Extra Strength Maalox Plus or Maalox TC Suspension. This medicine was prescribed for your particular condition. Do not use VIDEX for another condition or give it to others. Keep VIDEX and all medicines out of the reach of children. Throw away VIDEX when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink. This summary does not include everything there is to know about VIDEX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about VIDEX, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor. Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox® is a registered trademark of Novartis Consumer Health, Inc. Bristol-Myers Squibb Virology Bristol-Myers Squibb Company Princeton, NJ 08543 USA This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. xxxxxxxx Revised __________________ Based on xxxxx (xx/02) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Debra Birnkrant 9/25/02 04:03:13 PM NDA 20-156 NDA 20-155, NDA 20-154 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:46:53.848227	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20154s40,s41lbl.pdf', 'application_number': 20155, 'submission_type': 'SUPPL ', 'submission_number': 30}

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